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Cale JA, Chauhan EJ, Cleaver JJ, Fusciardi AR, McCann S, Waters HC, Žavbi J, King MV. GABAergic and inflammatory changes in the frontal cortex following neonatal PCP plus isolation rearing, as a dual-hit neurodevelopmental model for schizophrenia. Mol Neurobiol 2024; 61:6968-6983. [PMID: 38363536 PMCID: PMC11339149 DOI: 10.1007/s12035-024-03987-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Accepted: 01/24/2024] [Indexed: 02/17/2024]
Abstract
The pathogenesis of schizophrenia begins in early neurodevelopment and leads to excitatory-inhibitory imbalance. It is therefore essential that preclinical models used to understand disease, select drug targets and evaluate novel therapeutics encompass similar neurochemical deficits. One approach to improved preclinical modelling incorporates dual-hit neurodevelopmental insults, like neonatal administration of phencyclidine (PCP, to disrupt development of glutamatergic circuitry) then post-weaning isolation (Iso, to mimic adolescent social stress). We recently showed that male Lister-hooded rats exposed to PCP-Iso exhibit reduced hippocampal expression of the GABA interneuron marker calbindin. The current study expanded on this by investigating changes to additional populations of GABAergic interneurons in frontal cortical and hippocampal tissue from the same animals (by immunohistochemistry) as well as levels of GABA itself (via ELISA). Because inflammatory changes are also implicated in schizophrenia, we performed additional immunohistochemical evaluations of Iba-1 positive microglia as well as ELISA analysis of IL-6 in the same brain regions. Single-hit isolation-reared and dual-hit PCP-Iso rats both showed reduced parvalbumin immunoreactivity in the prelimbic/infralimbic region of the frontal cortex. However, this was more widespread in PCP-Iso, extending to the medial/ventral and lateral/dorsolateral orbitofrontal cortices. Loss of GABAergic markers was accompanied by increased microglial activation in the medial/ventral orbitofrontal cortices of PCP-Iso, together with frontal cortical IL-6 elevations not seen following single-hit isolation rearing. These findings enhance the face validity of PCP-Iso, and we advocate the use of this preclinical model for future evaluation of novel therapeutics-especially those designed to normalise excitatory-inhibitory imbalance or reduce neuroinflammation.
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Affiliation(s)
- Jennifer A Cale
- School of Life Sciences, The University of Nottingham, Medical School, Queen's Medical Centre, Nottingham, NG7 2UH, UK
| | - Ethan J Chauhan
- School of Life Sciences, The University of Nottingham, Medical School, Queen's Medical Centre, Nottingham, NG7 2UH, UK
| | - Joshua J Cleaver
- School of Life Sciences, The University of Nottingham, Medical School, Queen's Medical Centre, Nottingham, NG7 2UH, UK
| | - Anthoio R Fusciardi
- School of Life Sciences, The University of Nottingham, Medical School, Queen's Medical Centre, Nottingham, NG7 2UH, UK
| | - Sophie McCann
- School of Life Sciences, The University of Nottingham, Medical School, Queen's Medical Centre, Nottingham, NG7 2UH, UK
| | - Hannah C Waters
- School of Life Sciences, The University of Nottingham, Medical School, Queen's Medical Centre, Nottingham, NG7 2UH, UK
| | - Juš Žavbi
- School of Life Sciences, The University of Nottingham, Medical School, Queen's Medical Centre, Nottingham, NG7 2UH, UK
| | - Madeleine V King
- School of Life Sciences, The University of Nottingham, Medical School, Queen's Medical Centre, Nottingham, NG7 2UH, UK.
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2
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Spencer KM. Gamma Oscillations as a Biomarker of Neural Circuit Function in Psychosis: Where Are We, and Where Do We Go from Here? ADVANCES IN NEUROBIOLOGY 2024; 40:321-349. [PMID: 39562450 DOI: 10.1007/978-3-031-69491-2_12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/21/2024]
Abstract
This chapter is a selective and critical review of the literature on gamma oscillations in schizophrenia and related studies in other relevant fields that pertain to the hypothesis that abnormal gamma oscillations underlie symptoms of psychosis in individuals with schizophrenia. These gamma abnormalities result from deficient recurrent inhibition, in which parvalbumin-expressing, fast-spiking inhibitory interneurons do not receive sufficient excitation from N-methyl-D-aspartate receptors, resulting in a loss of phasic control over pyramidal cell spiking and impairment of gamma generation. The evidence for this hypothesis is critically reviewed, focusing on studies in the areas of visual feature binding, auditory steady-state response, and spontaneous gamma activity. The current state of the field is discussed, and recommendations for future directions are presented.
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Affiliation(s)
- Kevin M Spencer
- Research Service, VA Boston Healthcare System, Boston, MA, USA.
- Department of Psychiatry, Harvard Medical School, Boston, MA, USA.
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3
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Chen XL, Deng XT, Sun FG, Huang QJ. Effect of cognitive behavioral group therapy on rehabilitation of community patients with schizophrenia: A short-term randomized control trial. World J Psychiatry 2023; 13:583-592. [PMID: 37701538 PMCID: PMC10494774 DOI: 10.5498/wjp.v13.i8.583] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Revised: 07/17/2023] [Accepted: 07/19/2023] [Indexed: 08/17/2023] Open
Abstract
BACKGROUND The efficacy of cognitive behavioral group therapy (CBGT) for cognitive dys-function and negative symptoms of schizophrenia is established, but more evidence is required. AIM To assess the effectiveness of CBGT combined with mental health education as a treatment for schizophrenia compared with mental health education alone. METHODS In all, 120 schizophrenia out-patients were randomized into CBGT combined with mental health education or single mental health education. The primary outcomes were positive and negative symptoms, cognitive function, excitatory factor, anxiety and depression symptom improvements on the positive and negative syndrome scale score. Secondary outcome measures included social function and drug compliance. RESULTS There were significant differences between CBGT combined with mental health education and single mental health education on measures of positive and negative symptoms, cognitive functions, excitatory factor, anxiety and depression symptoms, and social functions. No other significant difference in outcomes was observed. CONCLUSION CBGT combined with mental health education may be relevant beneficial treatment method in reducing symptoms, cognitive and social functions of patients with schizophrenia.
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Affiliation(s)
- Xue-Lian Chen
- Medical College of Shantou University, Shantou 515041, Guangdong Province, China
- Chronic Disease Prevention and Control Center (Mental Health Center) of Longhua District, Shenzhen 518110, Guangdong Province, China
| | - Xiao-Ting Deng
- Chronic Disease Prevention and Control Center (Mental Health Center) of Longhua District, Shenzhen 518110, Guangdong Province, China
| | - Fu-Gang Sun
- Chronic Disease Prevention and Control Center (Mental Health Center) of Longhua District, Shenzhen 518110, Guangdong Province, China
| | - Qing-Jun Huang
- Mental Health Center, Shantou University, Shantou 515041, Guangdong Province, China
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Gawande DY, S Narasimhan KK, Shelkar GP, Pavuluri R, Stessman HAF, Dravid SM. GluN2D Subunit in Parvalbumin Interneurons Regulates Prefrontal Cortex Feedforward Inhibitory Circuit and Molecular Networks Relevant to Schizophrenia. Biol Psychiatry 2023; 94:297-309. [PMID: 37004850 PMCID: PMC10524289 DOI: 10.1016/j.biopsych.2023.03.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 03/01/2023] [Accepted: 03/21/2023] [Indexed: 04/04/2023]
Abstract
BACKGROUND Parvalbumin interneuron (PVI) activity synchronizes the medial prefrontal cortex circuit for normal cognitive function, and its impairment may contribute to schizophrenia (SZ). NMDA receptors in PVIs participate in these activities and form the basis for the NMDA receptor hypofunction hypothesis of SZ. However, the role of the GluN2D subunit, which is enriched in PVIs, in regulating molecular networks relevant to SZ is unknown. METHODS Using electrophysiology and a mouse model with conditional deletion of GluN2D from PVIs (PV-GluN2D knockout [KO]), we examined the cell excitability and neurotransmission in the medial prefrontal cortex. Histochemical, RNA sequencing analysis and immunoblotting were conducted to understand molecular mechanisms. Behavioral analysis was conducted to test cognitive function. RESULTS PVIs in the medial prefrontal cortex were found to express putative GluN1/2B/2D receptors. In a PV-GluN2D KO model, PVIs were hypoexcitable, whereas pyramidal neurons were hyperexcitable. Excitatory neurotransmission was higher in both cell types in PV-GluN2D KO, whereas inhibitory neurotransmission showed contrasting changes, which could be explained by reduced somatostatin interneuron projections and increased PVI projections. Genes associated with GABA (gamma-aminobutyric acid) synthesis, vesicular release, and uptake as well as those involved in formation of inhibitory synapses, specifically GluD1-Cbln4 and Nlgn2, and regulation of dopamine terminals were downregulated in PV-GluN2D KO. SZ susceptibility genes including Disc1, Nrg1, and ErbB4 and their downstream targets were also downregulated. Behaviorally, PV-GluN2D KO mice showed hyperactivity and anxiety behavior and deficits in short-term memory and cognitive flexibility. CONCLUSIONS These findings demonstrate that GluN2D in PVIs serves as a point of convergence of pathways involved in the regulation of GABAergic synapses relevant to SZ.
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Affiliation(s)
- Dinesh Y Gawande
- Department of Pharmacology and Neuroscience, Creighton University School of Medicine, Omaha, Nebraska
| | | | - Gajanan P Shelkar
- Department of Pharmacology and Neuroscience, Creighton University School of Medicine, Omaha, Nebraska
| | - Ratnamala Pavuluri
- Department of Pharmacology and Neuroscience, Creighton University School of Medicine, Omaha, Nebraska
| | - Holly A F Stessman
- Department of Pharmacology and Neuroscience, Creighton University School of Medicine, Omaha, Nebraska
| | - Shashank M Dravid
- Department of Pharmacology and Neuroscience, Creighton University School of Medicine, Omaha, Nebraska.
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5
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Tapias-Espinosa C, Sánchez-González A, Cañete T, Sampedro-Viana D, Castillo-Ruiz MDM, Oliveras I, Tobeña A, Aznar S, Fernández-Teruel A. Decreased activation of parvalbumin interneurons in the medial prefrontal cortex in intact inbred Roman rats with schizophrenia-like reduced sensorimotor gating. Behav Brain Res 2023; 437:114113. [PMID: 36108777 DOI: 10.1016/j.bbr.2022.114113] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 08/24/2022] [Accepted: 09/11/2022] [Indexed: 11/28/2022]
Abstract
Prepulse inhibition (PPI) allows assessing schizophrenia-like sensorimotor gating deficits in rodents. Previous studies indicate that PPI is modulated by the medial prefrontal cortex (mPFC), which is in agreement with our findings showing that PPI differences in the Roman rats are associated with divergences in mPFC activity. Here, we explore whether differences in PPI and mPFC activity in male Roman rats can be explained by (i) differences in the activation (c-Fos) of inhibitory neurons (parvalbumin (PV) interneurons); and/or (ii) reduced excitatory drive (PSD-95) to PV interneurons. Our data show that low PPI in the Roman high-avoidance (RHA) rats is associated with reduced activation of PV interneurons. Moreover, the RHA rats exhibit decreased density of both PV interneurons and PSD-95 puncta on active PV interneurons. These findings point to reduced cortical inhibition as a candidate to explain the schizophrenia-like features observed in RHA rats and support the role of impaired cortical inhibition in schizophrenia.
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Affiliation(s)
- Carles Tapias-Espinosa
- Department of Psychiatry & Forensic Medicine, Institute of Neurosciences, Universitat Autònoma de Barcelona, Barcelona, Spain.
| | - Ana Sánchez-González
- Department of Psychiatry & Forensic Medicine, Institute of Neurosciences, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Toni Cañete
- Department of Psychiatry & Forensic Medicine, Institute of Neurosciences, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Daniel Sampedro-Viana
- Department of Psychiatry & Forensic Medicine, Institute of Neurosciences, Universitat Autònoma de Barcelona, Barcelona, Spain
| | | | - Ignasi Oliveras
- Department of Psychiatry & Forensic Medicine, Institute of Neurosciences, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Adolf Tobeña
- Department of Psychiatry & Forensic Medicine, Institute of Neurosciences, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Susana Aznar
- Research Laboratory for Stereology and Neuroscience, Bispebjerg-Frederiksberg Hospital, University Hospital of Copenhagen, Copenhagen, Denmark; Copenhagen Center for Translational Research, Bispebjerg-Frederiksberg Hospital, University Hospital of Copenhagen, Copenhagen, Denmark.
| | - Alberto Fernández-Teruel
- Department of Psychiatry & Forensic Medicine, Institute of Neurosciences, Universitat Autònoma de Barcelona, Barcelona, Spain.
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6
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Chen-Engerer HJ, Jaeger S, Bondarenko R, Sprengel R, Hengerer B, Rosenbrock H, Mack V, Schuelert N. Increasing the Excitatory Drive Rescues Excitatory/Inhibitory Imbalance and Mismatch Negativity Deficit Caused by Parvalbumin Specific GluA1 Deletion. Neuroscience 2022; 496:190-204. [PMID: 35750109 DOI: 10.1016/j.neuroscience.2022.06.027] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 05/02/2022] [Accepted: 06/15/2022] [Indexed: 11/25/2022]
Abstract
Disturbance in synaptic excitatory and inhibitory (E/I) transmission in the prefrontal cortex is considered a critical factor for cognitive dysfunction, a core symptom in schizophrenia. However, the cortical network pathophysiology induced by E/I imbalance is not well characterized, and an effective therapeutic strategy is lacking. In this study, we simulated imbalanced cortical network by using mice with parvalbumin neuron (PV) specific knockout of GluA1 (AMPA receptor subunit 1) (Gria1-PV KO) as an experimental model. Applying high-content confocal imaging and electrophysiological recordings in the medial prefrontal cortex (mPFC), we found structural and functional alterations in the local network of Gria1-PV KO mice. Additionally, we applied electroencephalography (EEG) to assess potential deficits in mismatch negativity (MMN), the standard readout in the clinic for measuring deviance detection and sensory information processing. Gria1-PV KO animals exhibited abnormal theta oscillation and MMN, which is consistent with clinical findings in cognitively impaired patients. Remarkably, we demonstrated that the glycine transporter 1 (GlyT1) inhibitor, Bitopertin, ameliorates E/I imbalance, hyperexcitability, and sensory processing malfunction in Gria1-PV KO mice. Our results suggest that PV-specific deletion of GluA1 might be an experimental approach for back translating the E/I imbalance observed in schizophrenic patients. Our work offers a systematic workflow to understand the effect of GlyT1 inhibition in restoring cortical network activity from single cells to local brain circuitry. This study highlights that selectively boosting NMDA receptor-mediated excitatory drive to enhance the network inhibitory transmission from interneurons to pyramidal neurons (PYs) is a potential therapeutic strategy for restoring E/I imbalance-associated cognitive-related abnormality.
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Affiliation(s)
- Hsing-Jung Chen-Engerer
- Central Nervous System Disease Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorferstr. 65, 88397 Biberach Riß, Germany.
| | - Stefan Jaeger
- Central Nervous System Disease Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorferstr. 65, 88397 Biberach Riß, Germany
| | - Rimma Bondarenko
- Central Nervous System Disease Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorferstr. 65, 88397 Biberach Riß, Germany
| | - Rolf Sprengel
- Max Planck Institute for Medical Research at the Institute for Anatomy and Cell Biology at Heidelberg University, Germany
| | - Bastian Hengerer
- Central Nervous System Disease Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorferstr. 65, 88397 Biberach Riß, Germany
| | - Holger Rosenbrock
- Central Nervous System Disease Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorferstr. 65, 88397 Biberach Riß, Germany
| | - Volker Mack
- CardioMetabolic Disease Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorferstr. 65, 88397 Biberach Riß, Germany
| | - Niklas Schuelert
- Central Nervous System Disease Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorferstr. 65, 88397 Biberach Riß, Germany
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7
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Jiang Y, Patton MH, Zakharenko SS. A Case for Thalamic Mechanisms of Schizophrenia: Perspective From Modeling 22q11.2 Deletion Syndrome. Front Neural Circuits 2021; 15:769969. [PMID: 34955759 PMCID: PMC8693383 DOI: 10.3389/fncir.2021.769969] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Accepted: 11/10/2021] [Indexed: 12/12/2022] Open
Abstract
Schizophrenia is a severe, chronic psychiatric disorder that devastates the lives of millions of people worldwide. The disease is characterized by a constellation of symptoms, ranging from cognitive deficits, to social withdrawal, to hallucinations. Despite decades of research, our understanding of the neurobiology of the disease, specifically the neural circuits underlying schizophrenia symptoms, is still in the early stages. Consequently, the development of therapies continues to be stagnant, and overall prognosis is poor. The main obstacle to improving the treatment of schizophrenia is its multicausal, polygenic etiology, which is difficult to model. Clinical observations and the emergence of preclinical models of rare but well-defined genomic lesions that confer substantial risk of schizophrenia (e.g., 22q11.2 microdeletion) have highlighted the role of the thalamus in the disease. Here we review the literature on the molecular, cellular, and circuitry findings in schizophrenia and discuss the leading theories in the field, which point to abnormalities within the thalamus as potential pathogenic mechanisms of schizophrenia. We posit that synaptic dysfunction and oscillatory abnormalities in neural circuits involving projections from and within the thalamus, with a focus on the thalamocortical circuits, may underlie the psychotic (and possibly other) symptoms of schizophrenia.
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Affiliation(s)
| | | | - Stanislav S. Zakharenko
- Division of Neural Circuits and Behavior, Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, TN, United States
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Yuan F, Yu J, Liao G, Li J, Long T, Li Y, Chen D, Dai Q, Zhu X, Hu S, Qian Z. 18 F-2-fluoro-2-deoxy-D-glucose-positron emission tomography metabolic pattern assessment in the brain of betel quid dependent individuals. Addict Biol 2021; 26:e13043. [PMID: 33908137 DOI: 10.1111/adb.13043] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 03/23/2021] [Accepted: 03/30/2021] [Indexed: 11/29/2022]
Abstract
The primary objective of this study was to identify the metabolic pattern in the brains of betel quid dependent (BQD) individuals using 18 F-2-fluoro-2-deoxy-D-glucose-positron emission tomography (18 F-FDG-PET). A total of 42 individuals (16 BQD individuals and 26 healthy controls, HCs) enrolled at the Department of Nuclear Medicine of Xiangya Hospital underwent brain 18 F-FDG-PET. Group comparisons using statistical parametric mapping (SPM) were performed to identify the 18 F-FDG-PET patterns. Standardized uptake value ratios of anterior cingulate, frontal, thalamus, parietal, occipital, temporal and cerebellum were calculated by SPM. The characteristics of abnormal metabolism in brain regions were quantified using the xjView toolbox, and a 3-D brain map was drawn using BrainNet Viewer. We found significant metabolic reduction in the bilateral middle prefrontal cortex (PFC) and the left orbital frontal gyrus (OFC). In contrast, hypermetabolism was observed in the inferior cerebellum, fusiform, superior cerebellum, parahippocampal, vermis, lingual and thalamus. However, we found no significant difference between the BQD and HC group in the anterior cingulate, thalamus, cerebellum and frontal, temporal, parietal and occipital lobes. In summary, we found abnormal 18 F-FDG-PET metabolic pattern in BQD individuals, and this pattern may help the treatment of BQD.
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Affiliation(s)
- Fulai Yuan
- Health Management Center, Xiangya Hospital Central South University Changsha China
| | - Jie Yu
- Department of Nuclear Medicine, XiangYa Hospital Central South University Changsha China
| | - Guang Liao
- Department of Nuclear Medicine, XiangYa Hospital Central South University Changsha China
| | - Jian Li
- Department of Nuclear Medicine, XiangYa Hospital Central South University Changsha China
| | - Tingting Long
- Department of Nuclear Medicine, XiangYa Hospital Central South University Changsha China
| | - Yulai Li
- Department of Nuclear Medicine, XiangYa Hospital Central South University Changsha China
| | - Dengming Chen
- Department of Nuclear Medicine, XiangYa Hospital Central South University Changsha China
| | - Qionghai Dai
- Department of Automation, Tsinghua National Laboratory for Information Science and Technology Tsinghua University Beijing China
| | - Xueling Zhu
- Department of Radiology, Xiangya Hospital Central South University Changsha China
| | - Shuo Hu
- Department of Nuclear Medicine, XiangYa Hospital Central South University Changsha China
- Key Laboratory of Biological Nanotechnology of National Health Commission Changsha China
- National Clinical Research Center for Geriatric Diseases (XIANGYA) Changsha China
| | - Zhaoxin Qian
- Department of Emergency, XiangYa Hospital Central South University Changsha China
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9
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Phillips JM, Kambi NA, Redinbaugh MJ, Mohanta S, Saalmann YB. Disentangling the influences of multiple thalamic nuclei on prefrontal cortex and cognitive control. Neurosci Biobehav Rev 2021; 128:487-510. [PMID: 34216654 DOI: 10.1016/j.neubiorev.2021.06.042] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 04/13/2021] [Accepted: 06/09/2021] [Indexed: 10/21/2022]
Abstract
The prefrontal cortex (PFC) has a complex relationship with the thalamus, involving many nuclei which occupy predominantly medial zones along its anterior-to-posterior extent. Thalamocortical neurons in most of these nuclei are modulated by the affective and cognitive signals which funnel through the basal ganglia. We review how PFC-connected thalamic nuclei likely contribute to all aspects of cognitive control: from the processing of information on internal states and goals, facilitating its interactions with mnemonic information and learned values of stimuli and actions, to their influence on high-level cognitive processes, attentional allocation and goal-directed behavior. This includes contributions to transformations such as rule-to-choice (parvocellular mediodorsal nucleus), value-to-choice (magnocellular mediodorsal nucleus), mnemonic-to-choice (anteromedial nucleus) and sensory-to-choice (medial pulvinar). Common mechanisms appear to be thalamic modulation of cortical gain and cortico-cortical functional connectivity. The anatomy also implies a unique role for medial PFC in modulating processing in thalamocortical circuits involving other orbital and lateral PFC regions. We further discuss how cortico-basal ganglia circuits may provide a mechanism through which PFC controls cortico-cortical functional connectivity.
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Affiliation(s)
- Jessica M Phillips
- Department of Psychology, University of Wisconsin-Madison, 1202 W Johnson St., Madison, WI 53706, United States.
| | - Niranjan A Kambi
- Department of Psychology, University of Wisconsin-Madison, 1202 W Johnson St., Madison, WI 53706, United States
| | - Michelle J Redinbaugh
- Department of Psychology, University of Wisconsin-Madison, 1202 W Johnson St., Madison, WI 53706, United States
| | - Sounak Mohanta
- Department of Psychology, University of Wisconsin-Madison, 1202 W Johnson St., Madison, WI 53706, United States
| | - Yuri B Saalmann
- Department of Psychology, University of Wisconsin-Madison, 1202 W Johnson St., Madison, WI 53706, United States; Wisconsin National Primate Research Center, University of Wisconsin-Madison, 1202 Capitol Ct., Madison, WI 53715, United States.
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10
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Fujikawa R, Yamada J, Jinno S. Subclass imbalance of parvalbumin-expressing GABAergic neurons in the hippocampus of a mouse ketamine model for schizophrenia, with reference to perineuronal nets. Schizophr Res 2021; 229:80-93. [PMID: 33229224 DOI: 10.1016/j.schres.2020.11.016] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Revised: 06/24/2020] [Accepted: 11/12/2020] [Indexed: 11/29/2022]
Abstract
Impairments of parvalbumin-expressing GABAergic neurons (PV+ neurons) and specialized extracellular structures called perineuronal nets (PNNs) have been found in schizophrenic patients. In this study, we examined potential alterations in four subclasses of PV+ neurons colocalized with PNNs in the hippocampus of a mouse ketamine model for schizophrenia. Because biosynthesis of human natural killer-1 (HNK-1) is shown to be associated with the risk of schizophrenia, here we used mouse monoclonal Cat-315 antibody, which recognizes HNK-1 glycans on PNNs. Once-daily intraperitoneal injections of ketamine for seven consecutive days induced hyper-locomotor activity in the open field tests. The prepulse inhibition (PPI) test showed that PPI scores declined in ketamine-treated mice compared to vehicle-treated mice. The densities of PV+ neurons and Cat-315+ PNNs declined in the CA1 region of ketamine-treated mice. Interestingly, the density of Cat-315+/PV+ neurons was lower in ketamine-treated mice than in vehicle-treated mice, whereas the density of Cat-315-/PV+ neurons was not affected by ketamine. Among the four subclasses of PV+ neurons, the densities of Cat-315+/PV+ basket cells and Cat-315-/PV+ axo-axonic cells were lower in ketamine-treated mice than in vehicle-treated mice, while the densities of Cat-315-/PV+ basket cells and Cat-315+/PV+ axo-axonic cells were not affected by ketamine. Taken together, PNNs may not play a simple neuroprotective role against ketamine. Because different subclasses of PV+ neurons are considered to play distinct roles in the hippocampal neuronal network, the ketamine-induced subclass imbalance of PV+ neurons may result in abnormal network activity, which underlies the pathophysiology of schizophrenia.
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Affiliation(s)
- Risako Fujikawa
- Department of Anatomy and Neuroscience, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Jun Yamada
- Department of Anatomy and Neuroscience, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Shozo Jinno
- Department of Anatomy and Neuroscience, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
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11
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Al-Absi AR, Qvist P, Okujeni S, Khan AR, Glerup S, Sanchez C, Nyengaard JR. Layers II/III of Prefrontal Cortex in Df(h22q11)/+ Mouse Model of the 22q11.2 Deletion Display Loss of Parvalbumin Interneurons and Modulation of Neuronal Morphology and Excitability. Mol Neurobiol 2020; 57:4978-4988. [PMID: 32820460 DOI: 10.1007/s12035-020-02067-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Accepted: 08/09/2020] [Indexed: 11/26/2022]
Abstract
The 22q11.2 deletion has been identified as a risk factor for multiple neurodevelopmental disorders. Behavioral and cognitive impairments are common among carriers of the 22q11.2 deletion. Parvalbumin expressing (PV+) interneurons provide perisomatic inhibition of excitatory neuronal circuits through GABAA receptors, and a deficit of PV+ inhibitory circuits may underlie a multitude of the behavioral and functional deficits in the 22q11.2 deletion syndrome. We investigated putative deficits of PV+ inhibitory circuits and the associated molecular, morphological, and functional alterations in the prefrontal cortex (PFC) of the Df(h22q11)/+ mouse model of the 22q11.2 hemizygous deletion. We detected a significant decrease in the number of PV+ interneurons in layers II/III of PFC in Df(h22q11)/+ mice together with a reduction in the mRNA and protein levels of GABAA (α3), a PV+ putative postsynaptic receptor subunit. Pyramidal neurons from the same layers further experienced morphological reorganizations of spines and dendrites. Accordingly, a decrease in the levels of the postsynaptic density protein 95 (PSD95) and a higher neuronal activity in response to the GABAA antagonist bicuculline were measured in these layers in PFC of Df(h22q11)/+ mice compared with their wild-type littermates. Our study shows that a hemizygotic deletion of the 22q11.2 locus leads to deficit in the GABAergic control of network activity and involves molecular and morphological changes in both the inhibitory and excitatory synapses of parvalbumin interneurons and pyramidal neurons specifically in layers II/III PFC.
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Affiliation(s)
- Abdel-Rahman Al-Absi
- Centre for Molecular Morphology, Section for Stereology and Microscopy; Centre for Stochastic Geometry and Advanced Bioimaging, Department of Clinical Medicine, Aarhus University, Palle Juul Jensens Boulevard, 99 8200, Aarhus N, Denmark.
| | - Per Qvist
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
- iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark
- Centre for Integrative Sequencing, iSEQ, Aarhus University, Aarhus, Denmark
- Centre for Genomics and Personalized Medicine, CGPM, Aarhus University, Aarhus, Denmark
| | - Samora Okujeni
- Laboratory for Biomicrotechnology, Department of Microsystems Engineering IMTEK, University of Freiburg, Freiburg, Germany
| | - Ahmad Raza Khan
- Center of Functionally Integrative Neuroscience (CFIN), Aarhus University, Aarhus, Denmark
- Centre of Biomedical Research (CBMR), SGPGIMS Campus, Lucknow, India
| | - Simon Glerup
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
| | - Connie Sanchez
- Translational Neuropsychiatry Unit, Aarhus University, Aarhus, Denmark
| | - Jens R Nyengaard
- Centre for Molecular Morphology, Section for Stereology and Microscopy; Centre for Stochastic Geometry and Advanced Bioimaging, Department of Clinical Medicine, Aarhus University, Palle Juul Jensens Boulevard, 99 8200, Aarhus N, Denmark
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12
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Development of the MAM model of schizophrenia in mice: Sex similarities and differences of hippocampal and prefrontal cortical function. Neuropharmacology 2019; 144:193-207. [DOI: 10.1016/j.neuropharm.2018.10.026] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2018] [Revised: 10/06/2018] [Accepted: 10/19/2018] [Indexed: 12/31/2022]
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13
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Cortico-thalamic hypo- and hyperconnectivity extend consistently to basal ganglia in schizophrenia. Neuropsychopharmacology 2018; 43:2239-2248. [PMID: 29899404 PMCID: PMC6135808 DOI: 10.1038/s41386-018-0059-z] [Citation(s) in RCA: 74] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2017] [Revised: 03/27/2018] [Accepted: 03/28/2018] [Indexed: 12/14/2022]
Abstract
Schizophrenia is characterized by hypoconnectivity or decreased intrinsic functional connectivity (iFC) between prefrontal-limbic cortices and thalamic nuclei, as well as hyperconnectivity or increased iFC between primary-sensorimotor cortices and thalamic nuclei. However, cortico-thalamic iFC overlaps with larger, structurally defined cortico-striato-pallido-thalamo-cortical (CSPTC) circuits. If such an overlap is relevant for intrinsic hypo-/hyperconnectivity, it suggests (i) that patterns of cortico-subcortical hypo-/hyperconnectivity extend consistently from thalamus to basal ganglia nuclei; and (ii) such consistent hypo-/hyperconnectivity might link distinctively but consonant with different symptom dimensions, namely cognitive and psychotic impairments. To test this hypothesis, 57 patients with schizophrenia and 61 healthy controls were assessed by resting-state functional magnetic resonance imaging (fMRI) and clinical-behavioral testing. IFC from intrinsic cortical networks into thalamus, striatum, and pallidum was estimated by partial correlations between fMRI time courses. In patients, the salience network covering prefrontal-limbic cortices was hypoconnected with the mediodorsal thalamus and ventral parts of striatum and pallidum; these iFC-hypoconnectivity patterns were correlated both among each other and specifically with patients' impaired cognition. In contrast, the auditory-sensorimotor network covering primary-sensorimotor cortices was hyperconnected with the anterior ventral nucleus of the thalamus and dorsal parts of striatum and pallidum; these iFC-hyperconnectivity patterns were likewise correlated among each other and specifically with patients' psychotic symptoms. The results demonstrate that prefrontal-limbic hypoconnectivity and primary-sensorimotor hyperconnectivity extend consistently across subcortical nuclei and specifically across distinct symptom dimensions. Data support the model of consistent cortico-subcortical hypo-/hyperconnectivity within CSPTC circuits in schizophrenia.
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14
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Roccaro-Waldmeyer DM, Girard F, Milani D, Vannoni E, Prétôt L, Wolfer DP, Celio MR. Eliminating the VGlut2-Dependent Glutamatergic Transmission of Parvalbumin-Expressing Neurons Leads to Deficits in Locomotion and Vocalization, Decreased Pain Sensitivity, and Increased Dominance. Front Behav Neurosci 2018; 12:146. [PMID: 30072881 PMCID: PMC6058961 DOI: 10.3389/fnbeh.2018.00146] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2018] [Accepted: 06/26/2018] [Indexed: 11/13/2022] Open
Abstract
The calcium-binding protein parvalbumin (PV) is a recognized marker of short-axon GABA-ergic neurons in the cortex and the hippocampus. However in addition, PV is expressed by excitatory, glutamatergic neurons in various areas of the brain and spinal cord. Depending on the location of these neurons, loading of their synaptic vesicles with glutamate is mediated by either of three vesicular glutamate transporters (VGlut): VGlut1, VGlut2, or VGlut3. Driven by our interest in one of these glutamatergic/PV-expressing cell clusters-the lateral hypothalamic parvafox nucleus-we investigated the functions of this population of neurons by the selective deletion of VGlut2 expression in PV-expressing cells according to the Cre/Lox-approach. PV-Cre;VGlut2-Lox mutant mice are phenotypically characterized by deficits in locomotion and vocalization, by a decreased thermal nociception, and by an increased social dominance. We conducted a search of the Allen Brain Atlas for regions that might co-express the genes encoding PV and VGlut2, and that might thus contribute to the manifestation of the observed phenotypes. Our survey revealed several structures that could contribute to the deficits in locomotion and vocalization, such as the red, the subthalamic and the deep cerebellar nuclei. It also disclosed that a shift in the balance of afferental glutamatergic neurotransmission to the periaqueductal gray matter might be accountable for the decrease in sensitivity to pain and for the increase in social dominance. As a whole, this study broadens the state of knowledge about PV-expressing excitatory neurons.
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Affiliation(s)
- Diana M Roccaro-Waldmeyer
- Anatomy and Programme in Neuroscience, Department of Medicine, University of Fribourg, Fribourg, Switzerland
| | - Franck Girard
- Anatomy and Programme in Neuroscience, Department of Medicine, University of Fribourg, Fribourg, Switzerland
| | - Daniele Milani
- Anatomy and Programme in Neuroscience, Department of Medicine, University of Fribourg, Fribourg, Switzerland
| | - Elisabetta Vannoni
- Division of Functional Neuroanatomy, Institute of Anatomy, Department of Medicine, University of Zurich, Zurich, Switzerland
| | - Laurent Prétôt
- Anatomy and Programme in Neuroscience, Department of Medicine, University of Fribourg, Fribourg, Switzerland
| | - David P Wolfer
- Division of Functional Neuroanatomy, Institute of Anatomy, Department of Medicine, University of Zurich, Zurich, Switzerland.,Institute of Human Movement Sciences and Sport, Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland.,Neuroscience Center Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland
| | - Marco R Celio
- Anatomy and Programme in Neuroscience, Department of Medicine, University of Fribourg, Fribourg, Switzerland
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15
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Jiang DY, Wu Z, Forsyth CT, Hu Y, Yee SP, Chen G. GABAergic deficits and schizophrenia-like behaviors in a mouse model carrying patient-derived neuroligin-2 R215H mutation. Mol Brain 2018; 11:31. [PMID: 29859117 PMCID: PMC5984814 DOI: 10.1186/s13041-018-0375-6] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2018] [Accepted: 05/24/2018] [Indexed: 01/03/2023] Open
Abstract
Schizophrenia (SCZ) is a severe mental disorder characterized by delusion, hallucination, and cognitive deficits. We have previously identified from schizophrenia patients a loss-of-function mutation Arg215→His215 (R215H) of neuroligin 2 (NLGN2) gene, which encodes a cell adhesion molecule critical for GABAergic synapse formation and function. Here, we generated a novel transgenic mouse line with neuroligin-2 (NL2) R215H mutation. The single point mutation caused a significant loss of NL2 protein in vivo, reduced GABAergic transmission, and impaired hippocampal activation. Importantly, R215H KI mice displayed anxiety-like behavior, impaired pre-pulse inhibition (PPI), cognition deficits and abnormal stress responses, recapitulating several key aspects of schizophrenia-like behaviors. Our results demonstrate a significant impact of a single point mutation NL2 R215H on brain functions, providing a novel animal model for the study of schizophrenia and neuropsychiatric disorders.
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Affiliation(s)
- Dong-Yun Jiang
- Department of Biology, Huck Institutes of Life Sciences, Pennsylvania State University, University Park, PA 16802 USA
| | - Zheng Wu
- Department of Biology, Huck Institutes of Life Sciences, Pennsylvania State University, University Park, PA 16802 USA
| | - Cody Tieu Forsyth
- Department of Biology, Huck Institutes of Life Sciences, Pennsylvania State University, University Park, PA 16802 USA
| | - Yi Hu
- Department of Biology, Huck Institutes of Life Sciences, Pennsylvania State University, University Park, PA 16802 USA
| | - Siu-Pok Yee
- Department of Cell Biology, University of Connecticut Health center, Farmington, CT 06030 USA
| | - Gong Chen
- Department of Biology, Huck Institutes of Life Sciences, Pennsylvania State University, University Park, PA 16802 USA
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16
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Ouhaz Z, Fleming H, Mitchell AS. Cognitive Functions and Neurodevelopmental Disorders Involving the Prefrontal Cortex and Mediodorsal Thalamus. Front Neurosci 2018; 12:33. [PMID: 29467603 PMCID: PMC5808198 DOI: 10.3389/fnins.2018.00033] [Citation(s) in RCA: 102] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2017] [Accepted: 01/15/2018] [Indexed: 11/13/2022] Open
Abstract
The mediodorsal nucleus of the thalamus (MD) has been implicated in executive functions (such as planning, cognitive control, working memory, and decision-making) because of its significant interconnectivity with the prefrontal cortex (PFC). Yet, whilst the roles of the PFC have been extensively studied, how the MD contributes to these cognitive functions remains relatively unclear. Recently, causal evidence in monkeys has demonstrated that in everyday tasks involving rapid updating (e.g., while learning something new, making decisions, or planning the next move), the MD and frontal cortex are working in close partnership. Furthermore, researchers studying the MD in rodents have been able to probe the underlying mechanisms of this relationship to give greater insights into how the frontal cortex and MD might interact during the performance of these essential tasks. This review summarizes the circuitry and known neuromodulators of the MD, and considers the most recent behavioral, cognitive, and neurophysiological studies conducted in monkeys and rodents; in total, this evidence demonstrates that MD makes a critical contribution to cognitive functions. We propose that communication occurs between the MD and the frontal cortex in an ongoing, fluid manner during rapid cognitive operations, via the means of efference copies of messages passed through transthalamic routes; the conductance of these messages may be modulated by other brain structures interconnected to the MD. This is similar to the way in which other thalamic structures have been suggested to carry out forward modeling associated with rapid motor responding and visual processing. Given this, and the marked thalamic pathophysiology now identified in many neuropsychiatric disorders, we suggest that changes in the different subdivisions of the MD and their interconnections with the cortex could plausibly give rise to a number of the otherwise disparate symptoms (including changes to olfaction and cognitive functioning) that are associated with many different neuropsychiatric disorders. In particular, we will focus here on the cognitive symptoms of schizophrenia and suggest testable hypotheses about how changes to MD-frontal cortex interactions may affect cognitive processes in this disorder.
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Affiliation(s)
- Zakaria Ouhaz
- Department of Experimental Psychology, University of Oxford, Oxford, United Kingdom
| | - Hugo Fleming
- Department of Experimental Psychology, University of Oxford, Oxford, United Kingdom
| | - Anna S Mitchell
- Department of Experimental Psychology, University of Oxford, Oxford, United Kingdom
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17
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Deng D, Jian C, Lei L, Zhou Y, McSweeney C, Dong F, Shen Y, Zou D, Wang Y, Wu Y, Zhang L, Mao Y. A prenatal interruption of DISC1 function in the brain exhibits a lasting impact on adult behaviors, brain metabolism, and interneuron development. Oncotarget 2017; 8:84798-84817. [PMID: 29156684 PMCID: PMC5689574 DOI: 10.18632/oncotarget.21381] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2017] [Accepted: 09/03/2017] [Indexed: 02/03/2023] Open
Abstract
Mental illnesses like schizophrenia (SCZ) and major depression disorder (MDD) are devastating brain disorders. The SCZ risk gene, disrupted in schizophrenia 1 (DISC1), has been associated with neuropsychiatric conditions. However, little is known regarding the long-lasting impacts on brain metabolism and behavioral outcomes from genetic insults on fetal NPCs during early life. We have established a new mouse model that specifically interrupts DISC1 functions in NPCs in vivo by a dominant-negative DISC1 (DN-DISC1) with a precise temporal and spatial regulation. Interestingly, prenatal interruption of mouse Disc1 function in NPCs leads to abnormal depression-like deficit in adult mice. Here we took a novel unbiased metabonomics approach to identify brain-specific metabolites that are significantly changed in DN-DISC1 mice. Surprisingly, the inhibitory neurotransmitter, GABA, is augmented. Consistently, parvalbumin (PV) interneurons are increased in the cingulate cortex, retrosplenial granular cortex, and motor cortex. Interestingly, somatostatin (SST) positive and neuropeptide Y (NPY) interneurons are decreased in some brain regions, suggesting that DN-DISC1 expression affects the localization of interneuron subtypes. To further explore the cellular mechanisms that cause this change, DN-DISC1 suppresses proliferation and promotes the cell cycle exit of progenitors in the medial ganglionic eminence (MGE), whereas it stimulates ectopic proliferation of neighboring cells through cell non-autonomous effect. Mechanistically, it modulates GSK3 activity and interrupts Dlx2 activity in the Wnt activation. In sum, our results provide evidence that specific genetic insults on NSCs at a short period of time could lead to prolonged changes of brain metabolism and development, eventually behavioral defects.
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Affiliation(s)
- Dazhi Deng
- Department of Emergency, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, China.,Department of Biology, Pennsylvania State University, University Park, PA, USA
| | - Chongdong Jian
- Department of Biology, Pennsylvania State University, University Park, PA, USA.,Department of Neurology, First Affiliated Hospital, Guangxi Medical University, Nanning, Guangxi, China
| | - Ling Lei
- Department of Biology, Pennsylvania State University, University Park, PA, USA.,Health Examination Center, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, China
| | - Yijing Zhou
- Department of Biology, Pennsylvania State University, University Park, PA, USA
| | - Colleen McSweeney
- Department of Biology, Pennsylvania State University, University Park, PA, USA
| | - Fengping Dong
- Department of Biology, Pennsylvania State University, University Park, PA, USA
| | - Yilun Shen
- Department of Biology, Pennsylvania State University, University Park, PA, USA
| | - Donghua Zou
- Department of Neurology, The First People's Hospital of Nanning, Nanning, Guangxi, China
| | - Yonggang Wang
- Department of Neurology, School of Medicine, Renji Hospital, Shanghai Jiaotong University, Shanghai, China
| | - Yuan Wu
- Department of Neurology, First Affiliated Hospital, Guangxi Medical University, Nanning, Guangxi, China
| | - Limin Zhang
- CAS Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Centre for Magnetic Resonance in Wuhan, Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan, China
| | - Yingwei Mao
- Department of Biology, Pennsylvania State University, University Park, PA, USA
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18
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Antioxidant Treatment in Male Mice Prevents Mitochondrial and Synaptic Changes in an NMDA Receptor Dysfunction Model of Schizophrenia. eNeuro 2017; 4:eN-NWR-0081-17. [PMID: 28819639 PMCID: PMC5559903 DOI: 10.1523/eneuro.0081-17.2017] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2017] [Revised: 07/26/2017] [Accepted: 08/01/2017] [Indexed: 01/09/2023] Open
Abstract
Glutamate theories of schizophrenia suggest that the disease is associated with a loss of NMDA receptors, specifically on GABAergic parvalbumin-expressing interneurons (PVIs), leading to changes in the excitation-inhibition balance in the prefrontal cortex (PFC). Oxidative stress contributes to the loss of PVI and the development of schizophrenia. Here, we investigated whether the glutathione precursor N-acetyl cysteine (NAC) can prevent changes in synaptic transmission at pyramidal cells and PVIs that result from developmental NMDAR blockade and how these changes are related to mitochondrial dysfunction in the PFCs of mice. Perinatal treatment with ketamine induced persistent changes in the reduced glutathione/oxidized glutathione (glutathione disulfide) ratio in the medial PFC, indicating long-lasting increases in oxidative stress. Perinatal ketamine treatment also reduced parvalbumin expression, and it induced a decline in mitochondrial membrane potential, as well as elevations in mitochondrial superoxide levels. At the level of synaptic function ketamine reduced inhibition onto layer 2/3 pyramidal cells and increased excitatory drive onto PVI, indicating long-lasting disruptions in the excitation-inhibition balance. These changes were accompanied by layer-specific alterations in NMDAR function in PVIs. All of these changes were mitigated by coadministration of NAC. In addition, NAC given only during late adolescence was also able to restore normal mitochondria function and inhibition at pyramidal cells. These results show that ketamine-induced alterations in PFC physiology correlate with cell type-specific changes in mitochondria function. The ability of NAC to prevent or restore these changes supports the usefulness of antioxidant supplementation in the treatment of schizophrenia.
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19
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Palomero-Gallagher N, Zilles K. Cortical layers: Cyto-, myelo-, receptor- and synaptic architecture in human cortical areas. Neuroimage 2017; 197:716-741. [PMID: 28811255 DOI: 10.1016/j.neuroimage.2017.08.035] [Citation(s) in RCA: 119] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2017] [Revised: 08/08/2017] [Accepted: 08/11/2017] [Indexed: 12/16/2022] Open
Abstract
Cortical layers have classically been identified by their distinctive and prevailing cell types and sizes, as well as the packing densities of cell bodies or myelinated fibers. The densities of multiple receptors for classical neurotransmitters also vary across the depth of the cortical ribbon, and thus determine the neurochemical properties of cyto- and myeloarchitectonic layers. However, a systematic comparison of the correlations between these histologically definable layers and the laminar distribution of transmitter receptors is currently lacking. We here analyze the densities of 17 different receptors of various transmitter systems in the layers of eight cytoarchitectonically identified, functionally (motor, sensory, multimodal) and hierarchically (primary and secondary sensory, association) distinct areas of the human cerebral cortex. Maxima of receptor densities are found in different layers when comparing different cortical regions, i.e. laminar receptor densities demonstrate differences in receptorarchitecture between isocortical areas, notably between motor and primary sensory cortices, specifically the primary visual and somatosensory cortices, as well as between allocortical and isocortical areas. Moreover, considerable differences are found between cytoarchitectonical and receptor architectonical laminar patterns. Whereas the borders of cyto- and myeloarchitectonic layers are well comparable, the laminar profiles of receptor densities rarely coincide with the histologically defined borders of layers. Instead, highest densities of most receptors are found where the synaptic density is maximal, i.e. in the supragranular layers, particularly in layers II-III. The entorhinal cortex as an example of the allocortex shows a peculiar laminar organization, which largely deviates from that of all the other cortical areas analyzed here.
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Affiliation(s)
- Nicola Palomero-Gallagher
- Institute of Neuroscience and Medicine (INM-1), Research Centre Jülich, Jülich, Germany; Department of Psychiatry, Psychotherapy, and Psychosomatics, Medical Faculty, RWTH Aachen, Aachen, Germany; JARA - Translational Brain Medicine, Aachen, Germany.
| | - Karl Zilles
- Institute of Neuroscience and Medicine (INM-1), Research Centre Jülich, Jülich, Germany; Department of Psychiatry, Psychotherapy, and Psychosomatics, Medical Faculty, RWTH Aachen, Aachen, Germany; JARA - Translational Brain Medicine, Aachen, Germany.
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20
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Glausier JR, Roberts RC, Lewis DA. Ultrastructural analysis of parvalbumin synapses in human dorsolateral prefrontal cortex. J Comp Neurol 2017; 525:2075-2089. [PMID: 28074478 PMCID: PMC5397325 DOI: 10.1002/cne.24171] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2016] [Revised: 12/19/2016] [Accepted: 12/20/2016] [Indexed: 12/11/2022]
Abstract
Coordinated activity of neural circuitry in the primate dorsolateral prefrontal cortex (DLPFC) supports a range of cognitive functions. Altered DLPFC activation is implicated in a number of human psychiatric and neurological illnesses. Proper DLPFC activity is, in part, maintained by two populations of neurons containing the calcium-binding protein parvalbumin (PV): local inhibitory interneurons that form Type II synapses, and long-range glutamatergic inputs from the thalamus that form Type I synapses. Understanding the contributions of each PV neuronal population to human DLPFC function requires a detailed examination of their anatomical properties. Consequently, we performed an electron microscopic analysis of (1) the distribution of PV immunoreactivity within the neuropil, (2) the properties of dendritic shafts of PV-IR interneurons, (3) Type II PV-IR synapses from PV interneurons, and (4) Type I PV-IR synapses from long-range projections, within the superficial and middle laminar zones of the human DLPFC. In both laminar zones, Type II PV-IR synapses from interneurons comprised ∼60% of all PV-IR synapses, and Type I PV-IR synapses from putative thalamocortical terminals comprised the remaining ∼40% of PV-IR synapses. Thus, the present study suggests that innervation from PV-containing thalamic nuclei extends across superficial and middle layers of the human DLPFC. These findings contrast with previous ultrastructural studies in monkey DLPFC where Type I PV-IR synapses were not identified in the superficial laminar zone. The presumptive added modulation of DLPFC circuitry by the thalamus in human may contribute to species-specific, higher-order functions.
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Affiliation(s)
- Jill R. Glausier
- Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213
| | - Rosalinda C. Roberts
- Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294
| | - David A. Lewis
- Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213
- Department of Neuroscience, University of Pittsburgh School of Arts and Sciences, Pittsburgh, PA 15213
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21
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Skåtun KC, Kaufmann T, Brandt CL, Doan NT, Alnæs D, Tønnesen S, Biele G, Vaskinn A, Melle I, Agartz I, Andreassen OA, Westlye LT. Thalamo-cortical functional connectivity in schizophrenia and bipolar disorder. Brain Imaging Behav 2017; 12:640-652. [DOI: 10.1007/s11682-017-9714-y] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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22
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Giraldo-Chica M, Woodward ND. Review of thalamocortical resting-state fMRI studies in schizophrenia. Schizophr Res 2017; 180:58-63. [PMID: 27531067 PMCID: PMC5297399 DOI: 10.1016/j.schres.2016.08.005] [Citation(s) in RCA: 160] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2016] [Revised: 08/03/2016] [Accepted: 08/06/2016] [Indexed: 12/19/2022]
Abstract
Brain circuitry underlying cognition, emotion, and perception is abnormal in schizophrenia. There is considerable evidence that the neuropathology of schizophrenia includes the thalamus, a key hub of cortical-subcortical circuitry and an important regulator of cortical activity. However, the thalamus is a heterogeneous structure composed of several nuclei with distinct inputs and cortical connections. Limitations of conventional neuroimaging methods and conflicting findings from post-mortem investigations have made it difficult to determine if thalamic pathology in schizophrenia is widespread or limited to specific thalamocortical circuits. Resting-state fMRI has proven invaluable for understanding the large-scale functional organization of the brain and investigating neural circuitry relevant to psychiatric disorders. This article summarizes resting-state fMRI investigations of thalamocortical functional connectivity in schizophrenia. Particular attention is paid to the course, diagnostic specificity, and clinical correlates of thalamocortical network dysfunction.
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23
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Gomes FV, Rincón-Cortés M, Grace AA. Adolescence as a period of vulnerability and intervention in schizophrenia: Insights from the MAM model. Neurosci Biobehav Rev 2016; 70:260-270. [PMID: 27235082 PMCID: PMC5074867 DOI: 10.1016/j.neubiorev.2016.05.030] [Citation(s) in RCA: 85] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2016] [Revised: 05/24/2016] [Accepted: 05/24/2016] [Indexed: 11/30/2022]
Abstract
Adolescence is a time of extensive neuroanatomical, functional and chemical reorganization of the brain, which parallels substantial maturational changes in behavior and cognition. Environmental factors that impinge on the timing of these developmental factors, including stress and drug exposure, increase the risk for psychiatric disorders. Indeed, antecedents to affective and psychotic disorders, which have clinical and pathophysiological overlap, are commonly associated with risk factors during adolescence that predispose to these disorders. In the context of schizophrenia, psychosis typically begins in late adolescence/early adulthood, which has been replicated by animal models. Rats exposed during gestational day (GD) 17 to the mitotoxin methylazoxymethanol acetate (MAM) exhibit behavioral, pharmacological, and anatomical characteristics consistent with an animal model of schizophrenia. Here we provide an overview of adolescent changes within the dopamine system and the PFC and review recent findings regarding the effects of stress and cannabis exposure during the peripubertal period as risk factors for the emergence of schizophrenia-like deficits. Finally, we discuss peripubertal interventions appearing to circumvent the emergence of adult schizophrenia-like deficits.
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Affiliation(s)
- Felipe V Gomes
- Departments of Neuroscience, Psychiatry and Psychology, United States
| | | | - Anthony A Grace
- Departments of Neuroscience, Psychiatry and Psychology, United States.
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24
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Martin S, Lazzarini M, Dullin C, Balakrishnan S, Gomes FV, Ninkovic M, El Hady A, Pardo LA, Stühmer W, Del-Bel E. SK3 Channel Overexpression in Mice Causes Hippocampal Shrinkage Associated with Cognitive Impairments. Mol Neurobiol 2016; 54:1078-1091. [PMID: 26803493 PMCID: PMC5310555 DOI: 10.1007/s12035-015-9680-6] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2015] [Accepted: 12/23/2015] [Indexed: 12/11/2022]
Abstract
The dysfunction of the small-conductance calcium-activated K+ channel SK3 has been described as one of the factors responsible for the progress of psychoneurological diseases, but the molecular basis of this is largely unknown. This report reveals through use of immunohistochemistry and computational tomography that long-term increased expression of the SK3 small-conductance calcium-activated potassium channel (SK3-T/T) in mice induces a notable bilateral reduction of the hippocampal area (more than 50 %). Histological analysis showed that SK3-T/T mice have cellular disarrangements and neuron discontinuities in the hippocampal formation CA1 and CA3 neuronal layer. SK3 overexpression resulted in cognitive loss as determined by the object recognition test. Electrophysiological examination of hippocampal slices revealed that SK3 channel overexpression induced deficiency of long-term potentiation in hippocampal microcircuits. In association with these results, there were changes at the mRNA levels of some genes involved in Alzheimer’s disease and/or linked to schizophrenia, epilepsy, and autism. Taken together, these features suggest that augmenting the function of SK3 ion channel in mice may present a unique opportunity to investigate the neural basis of central nervous system dysfunctions associated with schizophrenia, Alzheimer’s disease, or other neuropsychiatric/neurodegenerative disorders in this model system. As a more detailed understanding of the role of the SK3 channel in brain disorders is limited by the lack of specific SK3 antagonists and agonists, the results observed in this study are of significant interest; they suggest a new approach for the development of neuroprotective strategies in neuropsychiatric/neurodegenerative diseases with SK3 representing a potential drug target.
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Affiliation(s)
- Sabine Martin
- Department of Molecular Biology of Neuronal Signals, Max Planck Institute of Experimental Medicine, Hermann-Rein-Strasse 3, 37075, Göttingen, Germany
- Center Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Göttingen, Germany
| | - Marcio Lazzarini
- Department of Molecular Biology of Neuronal Signals, Max Planck Institute of Experimental Medicine, Hermann-Rein-Strasse 3, 37075, Göttingen, Germany
| | - Christian Dullin
- Department of Diagnostic and Interventional Radiology, Georg-August University Medical Center, 37075, Göttingen, Germany
| | - Saju Balakrishnan
- Center Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Göttingen, Germany
- Department of Neuro- and Sensory Physiology, Georg-August University Medical Center, 37073, Göttingen, Germany
| | - Felipe V Gomes
- Department of Pharmacology, Medical School of Ribeirão Preto, University of São Paulo, 14040-900, Ribeirão Preto, Brazil
| | - Milena Ninkovic
- Department of Neurosurgery, Georg-August University Medical Center, 37075, Göttingen, Germany
| | - Ahmed El Hady
- Department of Molecular Biology of Neuronal Signals, Max Planck Institute of Experimental Medicine, Hermann-Rein-Strasse 3, 37075, Göttingen, Germany
- Bernstein Focus for Neurotechnology and Bernstein Center for Computational Neuroscience, Göttingen, Germany
- Theoretical Neurophysics, Department of Non-linear Dynamics, Max Planck Institute for Dynamics and Self-Organization, 37077, Göttingen, Germany
- The Interdisciplinary Collaborative Research Center 889 "Cellular Mechanisms of Sensory Processing", Göttingen, Germany
| | - Luis A Pardo
- Oncophysiology Group, Max Planck Institute of Experimental Medicine, 37075, Göttingen, Germany
| | - Walter Stühmer
- Department of Molecular Biology of Neuronal Signals, Max Planck Institute of Experimental Medicine, Hermann-Rein-Strasse 3, 37075, Göttingen, Germany.
- Center Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Göttingen, Germany.
- Bernstein Focus for Neurotechnology and Bernstein Center for Computational Neuroscience, Göttingen, Germany.
| | - Elaine Del-Bel
- Department of Morphology, Physiology and Pathology, CNPQ Research 1B (Biophysics, Biochemistry, Pharmacology and Neuroscience), University of São Paulo Dental School of Ribeirão Preto, Avenida do Café 3400, 14040-904, Ribeirão Preto, Brazil.
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Lewis DA, Glausier JR. Alterations in Prefrontal Cortical Circuitry and Cognitive Dysfunction in Schizophrenia. NEBRASKA SYMPOSIUM ON MOTIVATION. NEBRASKA SYMPOSIUM ON MOTIVATION 2016; 63:31-75. [PMID: 27627824 DOI: 10.1007/978-3-319-30596-7_3] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
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Brisch R, Bielau H, Saniotis A, Wolf R, Bogerts B, Krell D, Steiner J, Braun K, Krzyżanowska M, Krzyżanowski M, Jankowski Z, Kaliszan M, Bernstein HG, Gos T. Calretinin and parvalbumin in schizophrenia and affective disorders: a mini-review, a perspective on the evolutionary role of calretinin in schizophrenia, and a preliminary post-mortem study of calretinin in the septal nuclei. Front Cell Neurosci 2015; 9:393. [PMID: 26578879 PMCID: PMC4624860 DOI: 10.3389/fncel.2015.00393] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2015] [Accepted: 09/22/2015] [Indexed: 12/14/2022] Open
Abstract
OBJECTIVE The septal nuclei are important limbic regions that are involved in emotional behavior and connect to various brain regions such as the habenular complex. Both the septal nuclei and the habenular complex are involved in the pathology of schizophrenia and affective disorders. METHODS We characterized the number and density of calretinin-immunoreactive neurons in the lateral, medial, and dorsal subregions of the septal nuclei in three groups of subjects: healthy control subjects (N = 6), patients with schizophrenia (N = 10), and patients with affective disorders (N = 6). RESULTS Our mini-review of the combined role of calretinin and parvalbumin in schizophrenia and affective disorders summarizes 23 studies. We did not observe significant differences in the numbers of calretinin-immunoreactive neurons or neuronal densities in the lateral, medial, and dorsal septal nuclei of patients with schizophrenia or patients with affective disorders compared to healthy control subjects. CONCLUSIONS Most post-mortem investigations of patients with schizophrenia have indicated significant abnormalities of parvalbumin-immunoreactive neurons in various brain regions including the hippocampus, the anterior cingulate cortex, and the prefrontal cortex in schizophrenia. This study also provides an explanation from an evolutionary perspective for why calretinin is affected in schizophrenia.
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Affiliation(s)
- Ralf Brisch
- Department of Forensic Medicine, Medical University of Gdańsk Gdańsk, Poland
| | - Hendrik Bielau
- Department of Psychiatry and Psychotherapy, Otto-von-Guericke-University of Magdeburg Magdeburg, Germany
| | - Arthur Saniotis
- School of Medicine, The University of Adelaide Adelaide, SA, Australia ; Institute of Evolutionary Medicine, University of Zurich Zurich, Switzerland
| | - Rainer Wolf
- Department of Psychiatry and Psychotherapy, Ruhr University Bochum Bochum, Germany
| | - Bernhard Bogerts
- Department of Psychiatry and Psychotherapy, Otto-von-Guericke-University of Magdeburg Magdeburg, Germany ; Center for Behavioral Brain Sciences Magdeburg, Germany
| | - Dieter Krell
- Department of Psychiatry and Psychotherapy, Otto-von-Guericke-University of Magdeburg Magdeburg, Germany
| | - Johann Steiner
- Department of Psychiatry and Psychotherapy, Otto-von-Guericke-University of Magdeburg Magdeburg, Germany ; Center for Behavioral Brain Sciences Magdeburg, Germany
| | - Katharina Braun
- Center for Behavioral Brain Sciences Magdeburg, Germany ; Department of Zoology/Developmental Neurobiology, Institute of Biology, Otto-von-Guericke-University of Magdeburg Magdeburg, Germany
| | - Marta Krzyżanowska
- Department of Forensic Medicine, Medical University of Gdańsk Gdańsk, Poland
| | - Maciej Krzyżanowski
- Department of Forensic Medicine, Medical University of Gdańsk Gdańsk, Poland
| | - Zbigniew Jankowski
- Department of Forensic Medicine, Medical University of Gdańsk Gdańsk, Poland
| | - Michał Kaliszan
- Department of Forensic Medicine, Medical University of Gdańsk Gdańsk, Poland
| | - Hans-Gert Bernstein
- Department of Psychiatry and Psychotherapy, Otto-von-Guericke-University of Magdeburg Magdeburg, Germany
| | - Tomasz Gos
- Department of Forensic Medicine, Medical University of Gdańsk Gdańsk, Poland
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Turkheimer FE, Leech R, Expert P, Lord LD, Vernon AC. The brain's code and its canonical computational motifs. From sensory cortex to the default mode network: A multi-scale model of brain function in health and disease. Neurosci Biobehav Rev 2015; 55:211-22. [PMID: 25956253 DOI: 10.1016/j.neubiorev.2015.04.014] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2014] [Revised: 04/01/2015] [Accepted: 04/25/2015] [Indexed: 12/21/2022]
Affiliation(s)
| | - Robert Leech
- Division of Brain Sciences, Imperial College London, London, UK
| | - Paul Expert
- Institute of Psychiatry, King's College London, London, UK
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The role of the thalamus in schizophrenia from a neuroimaging perspective. Neurosci Biobehav Rev 2015; 54:57-75. [DOI: 10.1016/j.neubiorev.2015.01.013] [Citation(s) in RCA: 122] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2014] [Revised: 12/19/2014] [Accepted: 01/12/2015] [Indexed: 02/06/2023]
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Relationship between somatostatin and death receptor expression in the orbital frontal cortex in schizophrenia: a postmortem brain mRNA study. NPJ SCHIZOPHRENIA 2015; 1:14004. [PMID: 27336026 PMCID: PMC4849439 DOI: 10.1038/npjschz.2014.4] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/22/2014] [Revised: 10/20/2014] [Accepted: 10/20/2014] [Indexed: 11/09/2022]
Abstract
Background: Recently, we provided evidence showing reductions in GAD67 and Dlx mRNAs in the orbital frontal cortex (OFC) in schizophrenia. It is unknown whether these reductions relate mainly to somatostatin (SST) or parvalbumin (PV) mRNA expression changes, and/or whether these reductions are related to decreased SST mRNA+ interneuron density. Aims: To determine whether inhibitory interneuron deficits in the OFC from people with schizophrenia are greatest for SST or PV mRNAs, and whether any such deficits relate to mRNAs encoding cell death signalling molecules. Methods: Inhibitory interneuron mRNAs (SST; PV: in situ hybridization, quantitative PCR (qPCR)) and death signaling mRNAs [FAS receptor (FASR); TNFSF13: qPCR] were measured in control and schizophrenia subjects (38/38). SST mRNA+ interneuron-like cells were quantified in layer II in the gyrus rectus. Gray matter SST and PV mRNAs were correlated with interstitial white matter neuron (IWMN) density (GAD65/67; NeuN) and death signaling mRNAs. Results: SST mRNA was reduced in OFC layers I–VI in schizophrenia (both in situ and qPCR), with greatest deficit in layer II (67%). Layer II SST mRNA+ neuron density was reduced in schizophrenia (~29%). PV mRNA was reduced in layers III (18%) and IV (31%) with no significant diagnostic difference in PV mRNA measured by qPCR. FASR mRNA was increased in schizophrenia (34%). SST, but not PV, expression correlated negatively with FASR and TNFSF13 expressions and with IWMN density. Conclusions: Our study demonstrates that SST interneurons are predominantly linked to the inhibitory interneuron pathology in the OFC in schizophrenia and that increased death receptor signaling mRNAs relate to prominent laminar deficits in SST mRNA in the OFC in schizophrenia. We suggest that SST interneurons may be more vulnerable to increased death receptor signaling than PV interneurons.
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Kim JH, Son YD, Kim JH, Choi EJ, Lee SY, Lee JE, Cho ZH, Kim YB. Serotonin transporter availability in thalamic subregions in schizophrenia: a study using 7.0-T MRI with [(11)C]DASB high-resolution PET. Psychiatry Res 2015; 231:50-7. [PMID: 25465315 DOI: 10.1016/j.pscychresns.2014.10.022] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2014] [Revised: 06/23/2014] [Accepted: 10/26/2014] [Indexed: 10/24/2022]
Abstract
The serotonin transporter (SERT) is an integral protein that provides an index of serotonergic innervation. Until recently, few studies have investigated SERT binding in thalamic subregions in schizophrenia. The purpose of this study was to examine SERT availability in thalamic subdivisions (anterior nucleus, mediodorsal nucleus, and pulvinar) using 7.0-T magnetic resonance imaging (MRI) and high-resolution positron emission tomography (PET) with (11)C-3-amino-4-(2-dimethylaminomethylphenylthio)benzonitrile ([(11)C]DASB) in schizophrenia. Antipsychotic-free patients with schizophrenia (n=12) and healthy controls (n=15) underwent PET and MRI scans. For SERT availability, the binding potential with respect to non-displaceable compartment (BPND) was derived using the simplified reference tissue model (SRTM2). The analysis revealed that there were no significant differences in SERT availability between the two groups. In patients with schizophrenia, the severity of negative symptoms had a negative correlation with SERT availability in the anterior nucleus of the left thalamus. The present study did not reveal significant differences in SERT availability in thalamic subdivisions between patients with schizophrenia and control subjects. The association of SERT availability in the anterior nucleus with negative symptoms may suggest a role for the anterior thalamic nucleus in the pathophysiology of symptoms of schizophrenia. The ultra-high resolution imaging system could be an important asset for in vivo psychiatric research by combining structural and molecular information.
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Affiliation(s)
- Jong-Hoon Kim
- Department of Psychiatry, Gil Medical Center, Gachon University, Incheon, Republic of Korea; Neuroscience Research Institute, Gachon University, Incheon, Republic of Korea
| | - Young-Don Son
- Neuroscience Research Institute, Gachon University, Incheon, Republic of Korea; Department of Biomedical Engineering, College of Health Science, Gachon University, Incheon, Republic of Korea
| | - Jeong-Hee Kim
- Neuroscience Research Institute, Gachon University, Incheon, Republic of Korea
| | - Eun-Jung Choi
- Neuroscience Research Institute, Gachon University, Incheon, Republic of Korea
| | - Sang-Yoon Lee
- Neuroscience Research Institute, Gachon University, Incheon, Republic of Korea; Department of Radiological Science, College of Health Science, Gachon University, Incheon, Republic of Korea
| | - Jee Eun Lee
- Gachon University Graduate School of Medicine, Incheon, Republic of Korea
| | - Zang-Hee Cho
- Neuroscience Research Institute, Gachon University, Incheon, Republic of Korea
| | - Young-Bo Kim
- Neuroscience Research Institute, Gachon University, Incheon, Republic of Korea; Department of Neurosurgery, Gil Medical Center, Gachon University, Incheon, Republic of Korea.
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Gill KM, Grace AA. Corresponding decrease in neuronal markers signals progressive parvalbumin neuron loss in MAM schizophrenia model. Int J Neuropsychopharmacol 2014; 17:1609-19. [PMID: 24787547 PMCID: PMC4161636 DOI: 10.1017/s146114571400056x] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
Abstract
Alteration in normal hippocampal (HPC) function attributed to reduced parvalbumin (PV) expression has been consistently reported in schizophrenia patients and in animal models of schizophrenia. However, it is unclear whether there is an overall loss of interneurons as opposed to a reduction in activity-dependent PV content. Co-expression of PV and the constitutively expressed substance P (SP)-receptor protein has been utilized in other models to ascertain the degree of cell survival, as opposed to reduction in activity-dependent PV content, in the HPC. The present study measured the co-expression of PV and SP-receptors in the dentate and dorsal and ventral CA3 subregions of the HPC in the methylazoymethanol acetate (MAM) rat neurodevelopmental model of schizophrenia. In addition, these changes were compared at the post-natal day 27 (PND27) and post-natal day 240 (PND > 240) time points. Brains from PND27 and PND > 240 MAM (n = 8) and saline (SAL, n = 8) treated offspring were immunohistochemically processed for the co-expression of PV and SP-receptors. The dorsal dentate, dorsal CA3 and ventral CA3 subregions of PND27 and PND > 240 MAM rats demonstrated significant reductions in PV but not SP-receptor expression, signifying a loss of PV-content. In contrast, in the ventral dentate the co-expression of PV and SP-receptors was significantly reduced only in PND > 240 MAM animals, suggesting a reduction in cell number. While MAM-induced reduction of PV content occurs in CA3 of dorsal and ventral HPC, the most substantial loss of interneuron number is localized to the ventral dentate of PND > 240 animals. The disparate loss of PV in HPC subregions likely impacts intra-HPC network activity in MAM rats.
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Affiliation(s)
- Kathryn M Gill
- Departments of Neuroscience, Psychiatry and Psychology,University of Pittsburgh,Pittsburgh, PA 15260,USA
| | - Anthony A Grace
- Departments of Neuroscience, Psychiatry and Psychology,University of Pittsburgh,Pittsburgh, PA 15260,USA
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Why are cortical GABA neurons relevant to internal focus in depression? A cross-level model linking cellular, biochemical and neural network findings. Mol Psychiatry 2014; 19:966-977. [PMID: 25048001 PMCID: PMC4169738 DOI: 10.1038/mp.2014.68] [Citation(s) in RCA: 97] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2014] [Revised: 04/16/2014] [Accepted: 05/19/2014] [Indexed: 12/15/2022]
Abstract
Major depression is a complex and severe psychiatric disorder whose symptomatology encompasses a critical shift in awareness, especially in the balance from external to internal mental focus. This is reflected by unspecific somatic symptoms and the predominance of the own cognitions manifested in increased self-focus and rumination. We posit here that sufficient empirical data has accumulated to build a coherent biologic model that links these psychologic concepts and symptom dimensions to observed biochemical, cellular, regional and neural network deficits. Specifically, deficits in inhibitory γ-aminobutyric acid regulating excitatory cell input/output and local cell circuit processing of information in key brain regions may underlie the shift that is observed in depressed subjects in resting-state activities between the perigenual anterior cingulate cortex and the dorsolateral prefrontal cortex. This regional dysbalance translates at the network level in a dysbalance between default-mode and executive networks, which psychopathologically surfaces as a shift in focus from external to internal mental content and associated symptoms. We focus here on primary evidence at each of those levels and on putative mechanistic links between those levels. Apart from its implications for neuropsychiatric disorders, our model provides for the first time a set of hypotheses for cross-level mechanisms of how internal and external mental contents may be constituted and balanced in healthy subjects, and thus also contributes to the neuroscientific debate on the neural correlates of consciousness.
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Wyckhuys T, Wyffels L, Langlois X, Schmidt M, Stroobants S, Staelens S. The [18F]FDG μPET readout of a brain activation model to evaluate the metabotropic glutamate receptor 2 positive allosteric modulator JNJ-42153605. J Pharmacol Exp Ther 2014; 350:375-86. [PMID: 24898267 DOI: 10.1124/jpet.114.213959] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
Using [(18)F]fluorodeoxyglucose μ-positron emission tomography ([(18)F]FDG μPET), we compared subanesthetic doses of memantine and ketamine on their potential to induce increases in brain activation. We also studied the reversal effect of the well-known metabotropic glutamate receptor (mGluR)-2/3 agonist LY404039 [(-)-(1R,4S,5S,6S)-4-amino-2-sulfonylbicyclo[3.1.0]hexane-4,6-dicarboxylic acid] and the novel mGluR2 positive allosteric modulator (PAM) JNJ-42153605 [3-cylcopropylmethyl-7-(4-phenylpiperidin-1-yl)-8-trifluoromethyl [1,2,4] triazolo[4,3-a]pyridine]. First, rats (n = 12) were subjected to LY404039 (10 mg/kg s.c.) or vehicle, 30 minutes prior to saline, ketamine (30 mg/kg i.p.), or memantine (20 mg/kg i.p.). Second, rats (n = 12) were subjected to 2.5 mg/kg or 10 mg/kg mGluR2 PAM JNJ-42153605 or vehicle (s.c.), 30 minutes prior to memantine (20 mg/kg i.p.) or saline. Fifteen minutes later, [(18)F]FDG was injected (37 MBq i.v.) followed by a μPET/computed tomography scan. The increase due to memantine is significant for all relevant brain areas, whereas for ketamine this is not the case. Standard uptake values (SUVs) of the LY404039 pretreated and memantine-challenged group display a full reversal. Pretreatment with JNJ-42153605 also dose-dependently decreases SUV with a full reversal as well (for 10 mg/kg). Moreover, specificity of JNJ-42153605 is reached at this dose. In conclusion, this μPET experiment clearly indicates that subanesthetic doses of memantine induce significant increases of [(18)F]FDG SUVs in discrete brain areas and that the novel mGluR2 PAM has the capacity to dose-dependently and specifically reverse memantine-induced brain activation.
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Affiliation(s)
- Tine Wyckhuys
- Molecular Imaging Center Antwerp, University of Antwerp, Antwerp, Belgium (T.W., St.S.); Nuclear Medicine Department, University Hospital, Antwerp, Belgium (L.w., Si.S.); and Department of Neuroscience, Janssen Pharmaceutica NV, Beerse, Belgium (X.L., M.S.)
| | - Leonie Wyffels
- Molecular Imaging Center Antwerp, University of Antwerp, Antwerp, Belgium (T.W., St.S.); Nuclear Medicine Department, University Hospital, Antwerp, Belgium (L.w., Si.S.); and Department of Neuroscience, Janssen Pharmaceutica NV, Beerse, Belgium (X.L., M.S.)
| | - Xavier Langlois
- Molecular Imaging Center Antwerp, University of Antwerp, Antwerp, Belgium (T.W., St.S.); Nuclear Medicine Department, University Hospital, Antwerp, Belgium (L.w., Si.S.); and Department of Neuroscience, Janssen Pharmaceutica NV, Beerse, Belgium (X.L., M.S.)
| | - Mark Schmidt
- Molecular Imaging Center Antwerp, University of Antwerp, Antwerp, Belgium (T.W., St.S.); Nuclear Medicine Department, University Hospital, Antwerp, Belgium (L.w., Si.S.); and Department of Neuroscience, Janssen Pharmaceutica NV, Beerse, Belgium (X.L., M.S.)
| | - Sigrid Stroobants
- Molecular Imaging Center Antwerp, University of Antwerp, Antwerp, Belgium (T.W., St.S.); Nuclear Medicine Department, University Hospital, Antwerp, Belgium (L.w., Si.S.); and Department of Neuroscience, Janssen Pharmaceutica NV, Beerse, Belgium (X.L., M.S.)
| | - Steven Staelens
- Molecular Imaging Center Antwerp, University of Antwerp, Antwerp, Belgium (T.W., St.S.); Nuclear Medicine Department, University Hospital, Antwerp, Belgium (L.w., Si.S.); and Department of Neuroscience, Janssen Pharmaceutica NV, Beerse, Belgium (X.L., M.S.)
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Vernon AC, Crum WR, Lerch JP, Chege W, Natesan S, Modo M, Cooper JD, Williams SCR, Kapur S. Reduced cortical volume and elevated astrocyte density in rats chronically treated with antipsychotic drugs-linking magnetic resonance imaging findings to cellular pathology. Biol Psychiatry 2014; 75:982-90. [PMID: 24143881 DOI: 10.1016/j.biopsych.2013.09.012] [Citation(s) in RCA: 71] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2013] [Revised: 09/04/2013] [Accepted: 09/09/2013] [Indexed: 01/05/2023]
Abstract
BACKGROUND Increasing evidence suggests that antipsychotic drugs (APD) might affect brain structure directly, particularly the cerebral cortex. However, the precise anatomical loci of these effects and their underlying cellular basis remain unclear. METHODS With ex vivo magnetic resonance imaging in rats treated chronically with APDs, we used automated analysis techniques to map the regions that show maximal impact of chronic (8 weeks) treatment with either haloperidol or olanzapine on the rat cortex. Guided by these imaging findings, we undertook a focused postmortem investigation with stereology. RESULTS We identified decreases in the volume and thickness of the anterior cingulate cortex (ACC) after chronic APD treatment, regardless of the APD administered. Postmortem analysis confirmed these volumetric findings and demonstrated that chronic APD treatment had no effect on the total number of neurons or S100β+ astrocytes in the ACC. In contrast, an increase in the density of these cells was observed. CONCLUSIONS This study demonstrates region-specific structural effects of chronic APD treatment on the rat cortex, primarily but not exclusively localized to the ACC. At least in the rat, these changes are not due to a loss of either neurons or astrocytes and are likely to reflect a loss of neuropil. Although caution needs to be exerted when extrapolating results from animals to patients, this study highlights the power of this approach to link magnetic resonance imaging findings to their histopathological origins.
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Affiliation(s)
| | - William R Crum
- Department of Neuroimaging, Centre for Neuroimaging Sciences
| | - Jason P Lerch
- Mouse Imaging Centre, The Hospital for Sick Children and Department of Medical Biophysics, University of Toronto, Toronto, Canada
| | | | | | - Michel Modo
- Department of Neuroscience, Centre for the Cellular Basis of Behaviour, The James Black Centre, King's College London, Institute of Psychiatry
| | - Jonathan D Cooper
- Department of Neuroscience, Centre for the Cellular Basis of Behaviour, The James Black Centre, King's College London, Institute of Psychiatry
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Li P, Huntsman MM. Two functional inhibitory circuits are comprised of a heterogeneous population of fast-spiking cortical interneurons. Neuroscience 2014; 265:60-71. [PMID: 24480365 DOI: 10.1016/j.neuroscience.2014.01.033] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2013] [Revised: 01/15/2014] [Accepted: 01/17/2014] [Indexed: 02/05/2023]
Abstract
Cortical fast spiking (FS) interneurons possess autaptic, synaptic, and electrical synapses that serve to mediate a fast, coordinated response to their postsynaptic targets. While FS interneurons are known to participate in numerous and diverse actions, functional subgroupings within this multi-functional interneuron class remain to be identified. In the present study, we examined parvalbumin-positive FS interneurons in layer 4 of the primary somatosensory (barrel) cortex - a brain region well-known for specialized inhibitory function. Here we show that FS interneurons fall into two broad categories identified by the onset of the first action potential in a depolarizing train as: "delayed firing FS interneurons (FSD) and early onset firing FS interneurons (FSE). Subtle variations in action potential firing reveal six subtypes within these two categories: delayed non-accommodating (FSD-NAC), delayed stuttering (FSD-STUT), early onset stuttering (FSE-STUT), early onset-late spiking (FSE-LS), early onset early-spiking (FSE-ES), and early onset accommodating (FSE-AC). Using biophysical criteria previously employed to distinguish neuronal cell types, the FSD and FSE categories exhibit several shared biophysical and synaptic properties that coincide with the notion of specificity of inhibitory function within the cortical FS interneuron class.
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Affiliation(s)
- P Li
- Center for Neuroscience Research, Children's National Medical Center, Washington, DC 20010, USA
| | - M M Huntsman
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Pediatrics, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.
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Gill KM, Grace AA. The role of α5 GABAA receptor agonists in the treatment of cognitive deficits in schizophrenia. Curr Pharm Des 2014; 20:5069-76. [PMID: 24345268 PMCID: PMC4074253 DOI: 10.2174/1381612819666131216114612] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2013] [Accepted: 12/10/2013] [Indexed: 11/22/2022]
Abstract
Currently available pharmacotherapies for the treatment of schizophrenia are ineffective in restoring the disrupted cognitive function associated with this disorder. As such, there is a continued search for more viable novel drug targets. Engaging in cognitive behaviors is associated with distinct coordinated oscillatory activity across brain regions, in particular the hippocampus and prefrontal cortex. In schizophrenia patients, pathological alterations in the functionality of GABAergic interneurons in the PFC and HPC responsible for generating network oscillations are thought to contribute to impaired cognition. Destabilized GABAergic interneuron activity in the HPC is further associated with aberrant increases in HPC output and enhanced dopamine neuron activity. Consequently, drugs directed at restoring HPC function could impact both oscillatory activity along with dopamine tone. There is compelling evidence from animal models of schizophrenia that allosteric modulation of the α5 subunit of the GABAA receptor is a viable means of resolving aberrant dopamine system activity through indirect alteration of HPC output. Consequently, these compounds are promising for their potential in also ameliorating cognitive deficits attributed to dysfunction in HPC network activity.
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Affiliation(s)
| | - Anthony A Grace
- University of Pittsburgh, Department of Neuroscience, A210 Langley Hall, Pittsburgh, PA 15260, USA.
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Glausier JR, Fish KN, Lewis DA. Altered parvalbumin basket cell inputs in the dorsolateral prefrontal cortex of schizophrenia subjects. Mol Psychiatry 2014; 19:30-6. [PMID: 24217255 PMCID: PMC3874728 DOI: 10.1038/mp.2013.152] [Citation(s) in RCA: 118] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2013] [Revised: 08/26/2013] [Accepted: 09/30/2013] [Indexed: 01/08/2023]
Abstract
Cortical circuitry dysfunction in schizophrenia has been studied at many different levels of resolution, but not at the most basic unit of network organization--synaptic inputs. Multi-label electron or confocal light microscopy is required to examine specific types of synaptic inputs, and application of these methods to quantitatively study disease-related changes in human postmortem tissue has not been feasible for technical reasons. We recently developed a multi-label confocal light microscopic approach that makes possible the systematic identification and quantification of synaptic inputs, and of the relative levels of proteins localized to these inputs, in human postmortem tissue. We applied this approach to quantify parvalbumin basket cell (PVBC) inputs in area 9 of the dorsolateral prefrontal cortex from schizophrenia and matched comparison subjects. Tissue sections were triple-labeled for the 65 kD isoform of glutamic acid decarboxylase (GAD65), PV and the GABA(A) receptor α1 subunit. PVBC axonal boutons were defined as PV/GAD65 dual-labeled puncta, and PVBC inputs were defined as a PVBC bouton that overlapped a GABA(A) receptor α1 subunit punctum. The density of PVBC inputs was unchanged in subjects with schizophrenia, but levels of PV protein were lower in PVBC boutons. In concert with prior reports, these findings indicate that PVBC dysfunction in schizophrenia reflects molecular and not structural alterations in these cells and their axon terminals.
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Affiliation(s)
- JR Glausier
- Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - KN Fish
- Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - DA Lewis
- Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA,Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA
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Anticevic A, Cole MW, Repovs G, Savic A, Driesen NR, Yang G, Cho YT, Murray JD, Glahn DC, Wang XJ, Krystal JH. Connectivity, pharmacology, and computation: toward a mechanistic understanding of neural system dysfunction in schizophrenia. Front Psychiatry 2013; 4:169. [PMID: 24399974 PMCID: PMC3871997 DOI: 10.3389/fpsyt.2013.00169] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2013] [Accepted: 12/04/2013] [Indexed: 12/30/2022] Open
Abstract
Neuropsychiatric diseases such as schizophrenia and bipolar illness alter the structure and function of distributed neural networks. Functional neuroimaging tools have evolved sufficiently to reliably detect system-level disturbances in neural networks. This review focuses on recent findings in schizophrenia and bipolar illness using resting-state neuroimaging, an advantageous approach for biomarker development given its ease of data collection and lack of task-based confounds. These benefits notwithstanding, neuroimaging does not yet allow the evaluation of individual neurons within local circuits, where pharmacological treatments ultimately exert their effects. This limitation constitutes an important obstacle in translating findings from animal research to humans and from healthy humans to patient populations. Integrating new neuroscientific tools may help to bridge some of these gaps. We specifically discuss two complementary approaches. The first is pharmacological manipulations in healthy volunteers, which transiently mimic some cardinal features of psychiatric conditions. We specifically focus on recent neuroimaging studies using the NMDA receptor antagonist, ketamine, to probe glutamate synaptic dysfunction associated with schizophrenia. Second, we discuss the combination of human pharmacological imaging with biophysically informed computational models developed to guide the interpretation of functional imaging studies and to inform the development of pathophysiologic hypotheses. To illustrate this approach, we review clinical investigations in addition to recent findings of how computational modeling has guided inferences drawn from our studies involving ketamine administration to healthy subjects. Thus, this review asserts that linking experimental studies in humans with computational models will advance to effort to bridge cellular, systems, and clinical neuroscience approaches to psychiatric disorders.
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Affiliation(s)
- Alan Anticevic
- Department of Psychiatry, Yale University School of Medicine , New Haven, CT , USA ; NIAAA Center for the Translational Neuroscience of Alcoholism , New Haven, CT , USA ; Abraham Ribicoff Research Facilities, Connecticut Mental Health Center , New Haven, CT , USA ; Interdepartmental Neuroscience Program, Yale University , New Haven, CT , USA ; Olin Neuropsychiatry Research Center, Institute of Living, Hartford Hospital , Hartford, CT , USA ; Department of Psychology, Yale University , New Haven, CT , USA
| | - Michael W Cole
- Department of Psychology, Washington University in St. Louis , St. Louis, MO , USA
| | - Grega Repovs
- Department of Psychology, University of Ljubljana , Ljubljana , Slovenia
| | - Aleksandar Savic
- Department of Psychiatry, University of Zagreb School of Medicine , Zagreb , Croatia
| | - Naomi R Driesen
- Department of Psychiatry, Yale University School of Medicine , New Haven, CT , USA
| | - Genevieve Yang
- Department of Psychiatry, Yale University School of Medicine , New Haven, CT , USA ; Interdepartmental Neuroscience Program, Yale University , New Haven, CT , USA
| | - Youngsun T Cho
- Department of Psychiatry, Yale University School of Medicine , New Haven, CT , USA
| | - John D Murray
- Center for Neural Science, New York University , New York, NY , USA
| | - David C Glahn
- Department of Psychiatry, Yale University School of Medicine , New Haven, CT , USA ; Olin Neuropsychiatry Research Center, Institute of Living, Hartford Hospital , Hartford, CT , USA
| | - Xiao-Jing Wang
- Center for Neural Science, New York University , New York, NY , USA
| | - John H Krystal
- Department of Psychiatry, Yale University School of Medicine , New Haven, CT , USA ; NIAAA Center for the Translational Neuroscience of Alcoholism , New Haven, CT , USA ; Abraham Ribicoff Research Facilities, Connecticut Mental Health Center , New Haven, CT , USA ; Department of Neurobiology, Yale University School of Medicine , New Haven, CT , USA
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Del Pino I, García-Frigola C, Dehorter N, Brotons-Mas JR, Alvarez-Salvado E, Martínez de Lagrán M, Ciceri G, Gabaldón MV, Moratal D, Dierssen M, Canals S, Marín O, Rico B. Erbb4 deletion from fast-spiking interneurons causes schizophrenia-like phenotypes. Neuron 2013; 79:1152-68. [PMID: 24050403 DOI: 10.1016/j.neuron.2013.07.010] [Citation(s) in RCA: 230] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/05/2013] [Indexed: 01/09/2023]
Abstract
Genetic variation in neuregulin and its ErbB4 receptor has been linked to schizophrenia, although little is known about how they contribute to the disease process. Here, we have examined conditional Erbb4 mouse mutants to study how disruption of specific inhibitory circuits in the cerebral cortex may cause large-scale functional deficits. We found that deletion of ErbB4 from the two main classes of fast-spiking interneurons, chandelier and basket cells, causes relatively subtle but consistent synaptic defects. Surprisingly, these relatively small wiring abnormalities boost cortical excitability, increase oscillatory activity, and disrupt synchrony across cortical regions. These functional deficits are associated with increased locomotor activity, abnormal emotional responses, and impaired social behavior and cognitive function. Our results reinforce the view that dysfunction of cortical fast-spiking interneurons might be central to the pathophysiology of schizophrenia.
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Affiliation(s)
- Isabel Del Pino
- Instituto de Neurociencias, Consejo Superior de Investigaciones Científicas and Universidad Miguel Hernández, Sant Joan d'Alacant 03550, Spain
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Molecular evidence of N-methyl-D-aspartate receptor hypofunction in schizophrenia. Mol Psychiatry 2013; 18:1185-92. [PMID: 23070074 PMCID: PMC3807670 DOI: 10.1038/mp.2012.137] [Citation(s) in RCA: 184] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2012] [Revised: 07/05/2012] [Accepted: 08/20/2012] [Indexed: 11/16/2022]
Abstract
Blockade of N-methyl-D-aspartate receptors (NMDARs) produces behavior in healthy people that is similar to the psychotic symptoms and cognitive deficits of schizophrenia and can exacerbate symptoms in people with schizophrenia. However, an endogenous brain disruption of NMDARs has not been clearly established in schizophrenia. We measured mRNA transcripts for five NMDAR subunit mRNAs and protein for the NR1 subunit in the dorsolateral prefrontal cortex (DLPFC) of schizophrenia and control (n=74) brains. Five NMDAR single-nucleotide polymorphisms (SNPs) previously associated with schizophrenia were tested for association with NMDAR mRNAs in postmortem brain and for association with cognitive ability in an antemortem cohort of 101 healthy controls and 48 people with schizophrenia. The NR1 subunit (mRNA and protein) and NR2C mRNA were decreased in postmortem brain from people with schizophrenia (P=0.004, P=0.01 and P=0.01, respectively). In the antemortem cohort, the minor allele of NR2B rs1805502 (T5988C) was associated with significantly lower reasoning ability in schizophrenia. In the postmortem brain, the NR2B rs1805502 (T5988C) C allele was associated with reduced expression of NR1 mRNA and protein in schizophrenia. Reduction in NR1 and NR2C in the DLPFC of people with schizophrenia may lead to altered NMDAR stoichiometry and provides compelling evidence for an endogenous NMDAR deficit in schizophrenia. Genetic variation in the NR2B gene predicts reduced levels of the obligatory NR1 subunit, suggesting a novel mechanism by which the NR2B SNP may negatively influence other NMDAR subunit expression and reasoning ability in schizophrenia.
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41
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Schizophrenia-like phenotype of polysialyltransferase ST8SIA2-deficient mice. Brain Struct Funct 2013; 220:71-83. [DOI: 10.1007/s00429-013-0638-z] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2013] [Accepted: 09/10/2013] [Indexed: 10/26/2022]
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Anticevic A, Cole MW, Repovs G, Murray JD, Brumbaugh MS, Winkler AM, Savic A, Krystal JH, Pearlson GD, Glahn DC. Characterizing thalamo-cortical disturbances in schizophrenia and bipolar illness. Cereb Cortex 2013; 24:3116-30. [PMID: 23825317 DOI: 10.1093/cercor/bht165] [Citation(s) in RCA: 392] [Impact Index Per Article: 32.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Schizophrenia is a devastating neuropsychiatric syndrome associated with distributed brain dysconnectivity that may involve large-scale thalamo-cortical systems. Incomplete characterization of thalamic connectivity in schizophrenia limits our understanding of its relationship to symptoms and to diagnoses with shared clinical presentation, such as bipolar illness, which may exist on a spectrum. Using resting-state functional magnetic resonance imaging, we characterized thalamic connectivity in 90 schizophrenia patients versus 90 matched controls via: (1) Subject-specific anatomically defined thalamic seeds; (2) anatomical and data-driven clustering to assay within-thalamus dysconnectivity; and (3) machine learning to classify diagnostic membership via thalamic connectivity for schizophrenia and for 47 bipolar patients and 47 matched controls. Schizophrenia analyses revealed functionally related disturbances: Thalamic over-connectivity with bilateral sensory-motor cortices, which predicted symptoms, but thalamic under-connectivity with prefrontal-striatal-cerebellar regions relative to controls, possibly reflective of sensory gating and top-down control disturbances. Clustering revealed that this dysconnectivity was prominent for thalamic nuclei densely connected with the prefrontal cortex. Classification and cross-diagnostic results suggest that thalamic dysconnectivity may be a neural marker for disturbances across diagnoses. Present findings, using one of the largest schizophrenia and bipolar neuroimaging samples to date, inform basic understanding of large-scale thalamo-cortical systems and provide vital clues about the complex nature of its disturbances in severe mental illness.
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Affiliation(s)
- Alan Anticevic
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06511, USA NIAAA Center for the Translational Neuroscience of Alcoholism, New Haven, CT 06519, USA Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, New Haven, CT 06519, USA
| | - Michael W Cole
- Department of Psychology, Washington University in St. Louis, St. Louis, MO 63130, USA
| | - Grega Repovs
- Department of Psychology, University of Ljubljana, Ljubljana, Slovenia
| | - John D Murray
- Department of Neurobiology, Department of Physics, Yale University, New Haven, CT 06510, USA
| | - Margaret S Brumbaugh
- Olin Neuropsychiatry Research Center, Institute of Living, Hartford Hospital, CT 06106, USA
| | - Anderson M Winkler
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06511, USA Olin Neuropsychiatry Research Center, Institute of Living, Hartford Hospital, CT 06106, USA Oxford University, John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK and
| | - Aleksandar Savic
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06511, USA Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, New Haven, CT 06519, USA University Psychiatric Hospital Vrapce, University of Zagreb, Zagreb 10000, Croatia
| | - John H Krystal
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06511, USA NIAAA Center for the Translational Neuroscience of Alcoholism, New Haven, CT 06519, USA Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, New Haven, CT 06519, USA
| | - Godfrey D Pearlson
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06511, USA Department of Neurobiology, Olin Neuropsychiatry Research Center, Institute of Living, Hartford Hospital, CT 06106, USA
| | - David C Glahn
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06511, USA Olin Neuropsychiatry Research Center, Institute of Living, Hartford Hospital, CT 06106, USA
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Hagihara H, Takao K, Walton NM, Matsumoto M, Miyakawa T. Immature dentate gyrus: an endophenotype of neuropsychiatric disorders. Neural Plast 2013; 2013:318596. [PMID: 23840971 PMCID: PMC3694492 DOI: 10.1155/2013/318596] [Citation(s) in RCA: 96] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2013] [Revised: 04/17/2013] [Accepted: 04/19/2013] [Indexed: 12/13/2022] Open
Abstract
Adequate maturation of neurons and their integration into the hippocampal circuit is crucial for normal cognitive function and emotional behavior, and disruption of this process could cause disturbances in mental health. Previous reports have shown that mice heterozygous for a null mutation in α -CaMKII, which encodes a key synaptic plasticity molecule, display abnormal behaviors related to schizophrenia and other psychiatric disorders. In these mutants, almost all neurons in the dentate gyrus are arrested at a pseudoimmature state at the molecular and electrophysiological levels, a phenomenon defined as "immature dentate gyrus (iDG)." To date, the iDG phenotype and shared behavioral abnormalities (including working memory deficit and hyperlocomotor activity) have been discovered in Schnurri-2 knockout, mutant SNAP-25 knock-in, and forebrain-specific calcineurin knockout mice. In addition, both chronic fluoxetine treatment and pilocarpine-induced seizures reverse the neuronal maturation, resulting in the iDG phenotype in wild-type mice. Importantly, an iDG-like phenomenon was observed in post-mortem analysis of brains from patients with schizophrenia/bipolar disorder. Based on these observations, we proposed that the iDG is a potential endophenotype shared by certain types of neuropsychiatric disorders. This review summarizes recent data describing this phenotype and discusses the data's potential implication in elucidating the pathophysiology of neuropsychiatric disorders.
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Affiliation(s)
- Hideo Hagihara
- Division of Systems Medical Science, Institute for Comprehensive Medical Science, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi 470-1192, Japan
- CREST, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan
| | - Keizo Takao
- Division of Systems Medical Science, Institute for Comprehensive Medical Science, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi 470-1192, Japan
- CREST, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan
- Section of Behavior Patterns, Center for Genetic Analysis of Behavior, National Institute for Physiological Sciences, 5-1 Aza-Higashiyama, Myodaiji-cho, Okazaki, Aichi 444-8787, Japan
| | - Noah M. Walton
- CNS, Astellas Research Institute of America LLC, 8045 Lamon Avenue, Skokie, IL 60077, USA
| | - Mitsuyuki Matsumoto
- CNS, Astellas Research Institute of America LLC, 8045 Lamon Avenue, Skokie, IL 60077, USA
| | - Tsuyoshi Miyakawa
- Division of Systems Medical Science, Institute for Comprehensive Medical Science, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi 470-1192, Japan
- CREST, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan
- Section of Behavior Patterns, Center for Genetic Analysis of Behavior, National Institute for Physiological Sciences, 5-1 Aza-Higashiyama, Myodaiji-cho, Okazaki, Aichi 444-8787, Japan
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Fitzgerald ML, Mackie K, Pickel VM. The impact of adolescent social isolation on dopamine D2 and cannabinoid CB1 receptors in the adult rat prefrontal cortex. Neuroscience 2013; 235:40-50. [PMID: 23333674 DOI: 10.1016/j.neuroscience.2013.01.021] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2012] [Revised: 01/02/2013] [Accepted: 01/03/2013] [Indexed: 12/11/2022]
Abstract
Adolescent experiences of social deprivation result in profound and enduring perturbations in adult behavior, including impaired sensorimotor gating. The behavioral deficits induced by adolescent social isolation in rats can be ameliorated by antipsychotic drugs blocking dopamine D2 receptors in the prefrontal cortex (PFC) or by chronic administration of a cannabinoid CB1 receptor antagonist. The patterning and abundance of D2 receptors in the PFC evolves concurrently with CB1 receptors through the period of adolescence. This evidence suggests that mature expression and/or surface distribution of D2 and CB1 receptors may be influenced by the adolescent social environment. We tested this hypothesis using electron microscopic immunolabeling to compare the distribution of CB1 and D2 receptors in the PFC of adult male Sprague-Dawley rats that were isolated or socially reared throughout the adolescent transition period. Prepulse inhibition (PPI) of acoustic startle was assessed as a measure of sensorimotor gating. Social isolation reduced PPI and selectively decreased dendritic D2 immunogold labeling in the PFC. However, the decrease was only evident in dendrites that were not contacted by axon terminals containing CB1. There was no apparent change in the expression of CB1 or D2 receptors in presynaptic terminals. The D2 deficit therefore may be tempered by local CB1-mediated retrograde signaling. This suggests a biological mechanism whereby the adolescent social environment can persistently influence cortical dopaminergic activity and resultant behavior.
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Affiliation(s)
- M L Fitzgerald
- Department of Neuroscience, Brain and Mind Research Institute, Weill Cornell Medical College, 407 East 61st Street, New York, NY 10065, United States
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45
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Adams RA, Stephan KE, Brown HR, Frith CD, Friston KJ. The computational anatomy of psychosis. Front Psychiatry 2013; 4:47. [PMID: 23750138 PMCID: PMC3667557 DOI: 10.3389/fpsyt.2013.00047] [Citation(s) in RCA: 475] [Impact Index Per Article: 39.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2013] [Accepted: 05/16/2013] [Indexed: 11/13/2022] Open
Abstract
This paper considers psychotic symptoms in terms of false inferences or beliefs. It is based on the notion that the brain is an inference machine that actively constructs hypotheses to explain or predict its sensations. This perspective provides a normative (Bayes-optimal) account of action and perception that emphasizes probabilistic representations; in particular, the confidence or precision of beliefs about the world. We will consider hallucinosis, abnormal eye movements, sensory attenuation deficits, catatonia, and delusions as various expressions of the same core pathology: namely, an aberrant encoding of precision. From a cognitive perspective, this represents a pernicious failure of metacognition (beliefs about beliefs) that can confound perceptual inference. In the embodied setting of active (Bayesian) inference, it can lead to behaviors that are paradoxically more accurate than Bayes-optimal behavior. Crucially, this normative account is accompanied by a neuronally plausible process theory based upon hierarchical predictive coding. In predictive coding, precision is thought to be encoded by the post-synaptic gain of neurons reporting prediction error. This suggests that both pervasive trait abnormalities and florid failures of inference in the psychotic state can be linked to factors controlling post-synaptic gain - such as NMDA receptor function and (dopaminergic) neuromodulation. We illustrate these points using biologically plausible simulations of perceptual synthesis, smooth pursuit eye movements and attribution of agency - that all use the same predictive coding scheme and pathology: namely, a reduction in the precision of prior beliefs, relative to sensory evidence.
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Affiliation(s)
- Rick A Adams
- Wellcome Trust Centre for Neuroimaging, Institute of Neurology, University College London , London , UK
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46
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Abstract
Schizophrenia, a debilitating illness affecting 0.5-1% of the world's population, is characterized by positive, negative and cognitive symptoms. The latter are the best predictor of functional outcome, though largely untreated by current pharmacotherapy; thus a better understanding of the mechanisms underlying cognitive deficits in schizophrenia is crucial. Higher order cognitive processes, such as working memory, are associated with θ (4-7 Hz) and γ (30-80 Hz) oscillations in the prefrontal cortex (PFC), and subjects with schizophrenia exhibit working memory impairments and reduced cortical θ and γ band power. Cortical θ and γ oscillations are dependent on perisomatic inhibition of pyramidal neurons from basket cells expressing cholecystokinin (CCK(b) cells) and parvalbumin (PV(b) cells), respectively. Thus, alterations in basket cells may underlie the cortical oscillation deficits and working memory impairments in schizophrenia. Recent findings from postmortem studies suggest that schizophrenia is associated with multiple molecular alterations that regulate signalling from CCK(b) and PV(b) cells. These alterations include lower CCK and cannabinoid 1 receptor (CB1R) in CCK(b) cells, and lower glutamic acid decarboxylase 67 (GAD67) and increased μ opioid receptor (μOR) in PV(b) cells, as well as lower GABA(A) receptor α1 subunit in pyramidal neurons postsynaptic to PV(b) cells. These changes are thought to lead to increased and decreased strength, respectively, of CCK(b) and PV(b) cell-mediated inhibition of postsynaptic pyramidal cells. Therefore, a convergence of evidence suggests a substantial shift in the relative strengths of PFC pyramidal cell inhibition from CCK(b) and PV(b) cells that may underlie cortical oscillation deficits and working memory impairments in schizophrenia.
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Affiliation(s)
- Allison A Curley
- Translational Neuroscience Program, Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15213, USA
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47
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Lewis DA, Curley AA, Glausier JR, Volk DW. Cortical parvalbumin interneurons and cognitive dysfunction in schizophrenia. Trends Neurosci 2011; 35:57-67. [PMID: 22154068 DOI: 10.1016/j.tins.2011.10.004] [Citation(s) in RCA: 822] [Impact Index Per Article: 58.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2011] [Revised: 10/07/2011] [Accepted: 10/24/2011] [Indexed: 12/21/2022]
Abstract
Deficits in cognitive control, a core disturbance of schizophrenia, appear to emerge from impaired prefrontal gamma oscillations. Cortical gamma oscillations require strong inhibitory inputs to pyramidal neurons from the parvalbumin basket cell (PVBC) class of GABAergic neurons. Recent findings indicate that schizophrenia is associated with multiple pre- and postsynaptic abnormalities in PVBCs, each of which weakens their inhibitory control of pyramidal cells. These findings suggest a new model of cortical dysfunction in schizophrenia in which PVBC inhibition is decreased to compensate for an upstream deficit in pyramidal cell excitation. This compensation is thought to rebalance cortical excitation and inhibition, but at a level insufficient to generate the gamma oscillation power required for high levels of cognitive control.
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Affiliation(s)
- David A Lewis
- Translational Neuroscience Program, Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15213, USA.
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Leppä E, Linden AM, Vekovischeva OY, Swinny JD, Rantanen V, Toppila E, Höger H, Sieghart W, Wulff P, Wisden W, Korpi ER. Removal of GABA(A) receptor γ2 subunits from parvalbumin neurons causes wide-ranging behavioral alterations. PLoS One 2011; 6:e24159. [PMID: 21912668 PMCID: PMC3166293 DOI: 10.1371/journal.pone.0024159] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2011] [Accepted: 08/01/2011] [Indexed: 11/28/2022] Open
Abstract
We investigated the behavioral significance of fast synaptic inhibition by αβγ2-type GABAA receptors on parvalbumin (Pv) cells. The GABAA receptor γ2 subunit gene was selectively inactivated in Pv-positive neurons by Cre/loxP recombination. The resulting Pv-Δγ2 mice were relatively healthy in the first postnatal weeks; but then as Cre started to be expressed, the mice progressively developed wide-ranging phenotypic alterations including low body weight, motor deficits and tremor, decreased anxiety levels, decreased pain sensitivity and deficient prepulse inhibition of the acoustic startle reflex and impaired spatial learning. Nevertheless, the deletion was not lethal, and mice did not show increased mortality even after one year. Autoradiography with t-butylbicyclophosphoro[35S]thionate suggested an increased amount of GABAA receptors with only α and β subunits in central nervous system regions that contained high levels of parvalbumin neurons. Using BAC-transgenesis, we reduced some of the Pv-Δγ2 phenotype by selectively re-expressing the wild-type γ2 subunit back into some Pv cells (reticular thalamic neurons and cerebellar Pv-positive neurons). This produced less severe impairments of motor skills and spatial learning compared with Pv-Δγ2 mice, but all other deficits remained. Our results reveal the widespread significance of fast GABAergic inhibition onto Pv-positive neurons for diverse behavioral modalities, such as motor coordination, sensorimotor integration, emotional behavior and nociception.
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Affiliation(s)
- Elli Leppä
- Institute of Biomedicine, Pharmacology, University of Helsinki, Helsinki, Finland
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Selective pyramidal cell reduction of GABA(A) receptor α1 subunit messenger RNA expression in schizophrenia. Neuropsychopharmacology 2011; 36:2103-10. [PMID: 21677653 PMCID: PMC3158308 DOI: 10.1038/npp.2011.102] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Levels of messenger RNA (mRNA) for the α1 subunit of the GABA(A) receptor, which is present in 60% of cortical GABA(A) receptors, have been reported to be lower in layer 3 of the prefrontal cortex (PFC) in subjects with schizophrenia. This subunit is expressed in both pyramidal cells and interneurons, and thus lower α1 subunit levels in each cell population would have opposite effects on net cortical excitation. We used dual-label in situ hybridization to quantify GABA(A) α1 subunit mRNA expression in calcium/calmodulin-dependent kinase II α (CaMKIIα)-containing pyramidal cells and glutamic acid decarboxylase 65 kDa (GAD65)-containing interneurons in layer 3 of the PFC from matched schizophrenia and healthy comparison subjects. In subjects with schizophrenia, mean GABA(A) α1 subunit mRNA expression was significantly 40% lower in pyramidal cells, but was not altered in interneurons. Lower α1 subunit mRNA expression in pyramidal cells was not attributable to potential confounding factors, and thus appeared to reflect the disease process of schizophrenia. These results suggest that pyramidal cell inhibition is reduced in schizophrenia, whereas inhibition of GABA neurons is maintained. The cell type specificity of these findings may reflect a compensatory response to enhance layer 3 pyramidal cell activity in the face of the diminished excitatory drive associated with the lower dendritic spine density on these neurons.
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50
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Volk DW, Radchenkova PV, Walker EM, Sengupta EJ, Lewis DA. Cortical opioid markers in schizophrenia and across postnatal development. ACTA ACUST UNITED AC 2011; 22:1215-23. [PMID: 21810780 DOI: 10.1093/cercor/bhr202] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Certain cognitive deficits in schizophrenia have been linked to dysfunction of prefrontal cortical (PFC) γ-aminobutyric acid (GABA) neurons and appear neurodevelopmental in nature. Since opioids suppress GABA neuron activity, we conducted the first study to determine 1) whether the μ opioid receptor (MOR), δ opioid receptor (DOR), and opioid ligand proenkephalin are altered in the PFC of a large cohort of schizophrenia subjects and 2) the postnatal developmental trajectory in monkey PFC of opioid markers that are altered in schizophrenia. We used quantitative polymerase chain reaction to measure mRNA levels from 42 schizophrenia and 42 matched healthy comparison subjects; 18 monkeys chronically exposed to haloperidol, olanzapine, or placebo; and 49 monkeys aged 1 week-11.5 years. We found higher levels for MOR mRNA (+27%) in schizophrenia but no differences in DOR or proenkephalin mRNAs. Elevated MOR mRNA levels in schizophrenia did not appear to be explained by substance abuse, psychotropic medications, or illness chronicity. Finally, MOR mRNA levels declined through early postnatal development, stabilized shortly before adolescence and increased across adulthood in monkey PFC. In schizophrenia, higher MOR mRNA levels may contribute to suppressed PFC GABA neuron activity and might be attributable to alterations in the postnatal developmental trajectory of MOR signaling.
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Affiliation(s)
- David W Volk
- Department of Psychiatry, University of Pittsburgh, W1655 BST, 3811 O’Hara Street, Pittsburgh, PA 15213, USA.
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